Research ArticleIntegrating In Silico and In Vitro Approaches to Screen theAntidiabetic Properties from Tabernaemontana divaricata(Jasmine) Flowers

Saima Muzammil 1 Rahat Andleeb2 Sumreen Hayat1 Muhammad Umar Ijaz3

Asma Ashraf 2 Nimrah Zafar2 Shabana Naz2 and Mubashera Shaheen2

1Department of Microbiology Government College University Faisalabad Pakistan2Department of Zoology Government College University Faisalabad Pakistan3Department of Zoology Wildlife and Fisheries University of Agriculture Faisalabad Pakistan

Correspondence should be addressed to Asma Ashraf asmabinmgmailcom

Received 17 January 2022 Revised 28 February 2022 Accepted 17 March 2022 Published 31 May 2022

Academic Editor Fernanda Tonelli

Copyright copy 2022 Saima Muzammil et al )is is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited

)e purpose of this study was to assess different in vitro biological activities such as phytochemical constituents enzymaticantioxidant status cytotoxicity through hemolytic activity and antidiabetic potential of plant methanolic extract through glucoseuptake by yeast cells Further using in silico approach by the SwissADME technique the drug-likeness rules for bioactivecomponents were characterized while potential interactions were identified via molecular docking of a ligand with target proteinsby GOLD 530)e results showed that T divaricatawas rich in TPC and TFC ie 6232plusmn 402 and 2453plusmn 061 respectively andthe cytotoxic potential was 10 towards human RBCs while protein estimation revealed the presence of protein in the extractwhich was 2282plusmn 46 DPPH assay in comparison with ascorbic acid and several enzymatic assays such as CAT SOD and PODshowed maximum antioxidant potential ie159plusmn 233 6557plusmn 134 302plusmn 34 1587plusmn 05 and 074plusmn 02 respectivelyGlucose uptake by yeast cells ie α-amylase and α-glucosidase showed a maximum antidiabetic potential such as 7511plusmn 1444181plusmn 375 and 359plusmn 124 respectively Our results indicate that the methanolic extract of T divaricata has antioxidantpotential and inhibits α-amylase and α-glucosidase activity and possesses maximum antidiabetic potential )e results providescientific proof that the medicinal plant being studied is a powerful source of natural antioxidant antidiabetic and medicinallysignificant substances In silico study using a molecular docking unveiled that two compounds showed good interactions with5kzw protein with considerable binding affinities and fulfilled docking parameters It may conclude that T divaricata is animportant vegetable with a potent source of natural antioxidants and antidiabetic activity justifying its traditional use ingreen therapeutics

1 Introduction

Diabetes is a metabolic disorder characterized by a high levelof glucose in the bloodstream triggered by inadequate in-sulin output or insulin activity [1] Diabetes is a dynamicchronic disease needing ongoing medical care with harmreduction approaches within glycemic control [2] Polyuriapolydipsia dry mouth itchy skin blurry vision nausea andexhaustion are the typical physical symptoms of DM [3]Diabetes accounts for over 38 million deaths annually and is

therefore the fifth leading cause of mortality [4] )is diseaseis becoming disastrously underdeveloped (low-income)countries [5] Pakistan is amongst the ten countries that areexpected to have high figures of people with diabetes by 2030[6]

Diabetes increases the risk of several health problemsand has a severe effect on the eye kidney foot bloodpressure etc [2] α-Amylase involves the starch hydrolysisinto the small scraps of sugar [7] During diabetes ROS areinduced and cause β-cell glucose toxicity [8] Cytotoxic

HindawiEvidence-Based Complementary and Alternative MedicineVolume 2022 Article ID 4616815 17 pageshttpsdoiorg10115520224616815

T lymphocytes (CTLs) are one of the types of T cells andCTLs are triggered to clear cells associated with the virus [9]

Oxidative stress is caused by an increase in reactiveoxygen species which is the primary cause of diabetes andcan have serious consequences Enzymes including super-oxide dismutase glutathione peroxidase and catalase areinvolved in enzymatic defense systems [10 11] )e per-oxidases are a family of enzymes with the ability to oxidizedifferent substrates using H2O2 [12] Antioxidants (egsuperoxide dismutase (SOD) reduced glutathione (GSH)and other antioxidant enzymes) are generally providingtools to investigate the stress-related diabetes [13] Severalnatural antioxidants are present in plants and usually theseare vitamins C and E tannins and flavonoids )ese anti-oxidants have the competency to sustain or uphold β-celladministration and in this way they could diminish theglucose level in the blood It has been found that medicinalplants eg Coriandrum sativum Fraxinus excelsiorCasearia esculenta Caesalpinia bonducella and Biophytumsensitivum are more cost-effective have fewer side effectsand are more persuasive in curing diabetes mellitus thanconventional drugs [14]

Due to the high cost of pharmaceuticals typical andtraditional plants could be used to cure different diseases as70 to 80 of the developing world depends on them [15] Forthis purpose 800 plants could be considered for their an-tidiabetic potential [16] A plant species known as Taber-naemontana divaricata (TD) belongs to the familyApocynaceae locally acknowledged as TagarChandniCrepeJasmine In contrast to Staphylococcus aureus and Escher-ichia coli Tabernaemontana divaricata flower extract hasstrong antibacterial activity [17]

In silico approaches to the drug design has the benefit ofreducing the time and expense of developing new targets Insilico methods that can describe interacting molecules andpredict three-dimensional (3D) structures have been used tosolve several biological problems In this context this studyaimed to evaluate the phyto-components total phenoliccontent (TPC) total flavonoid content (TFC) and in vitrobiological properties such as DPPH (22-diphenyl-1-pic-rylhydrazyl) free radical scavenging enzymatic antioxidantactivities hemolysis and antidiabetic potentials of meth-anolic extract of T divaricate flower Further to developeffective inhibitors in silico analysis was performed to de-termine the interaction of identified antidiabetic compoundswith the target protein

2 Material and Methods

21 Determination of Total Phenolic and Flavonoid Contents(TPCandTFC) By following the protocol of Singleton et al[18] the TPC of methanolic extract of T divaricata wasevaluated )e absorbance for the mixtures of solutions wasmeasured at 760 nm with gallic acid as a standard and TPCresults were expressed as milligram gallic acid equivalent pergram dry weight (mg GAEg dw) in triplicates

)e procedure of Bao et al [19] was followed to calculatethe total flavonoid content (TFC) of T divaricata Even-tually the absorbance of the mixtures was measured against

a reagent blank at 510 nm and TFC was noted in triplicatesamples and presented as milligram quercetin per gram dryweight (mg QEg dw)

22 Antioxidant Activity Assays

221 DPPH Free Radical Scavenging Assay By following theprotocol of Gyamfi et al [20] the free radical scavengingcapability of T divaricata flower methanolic extract wasevaluated against free radicals of DPPH Ascorbic acid wasused as a standard )e following formula was used tocalculate the percentage inhibition of plant extract againstDPPH free radicals

Inhibition percentage of extract AB minus AS

AB1113890 1113891 times 100 (1)

where AB is the absorbance of blank and AS is the absor-bance of the sample

222 Enzymatic Antioxidant Activities )e method pro-posed by Mohebbi et al [20] was performed to measurethe catalase (CAT) activity In this method 01mL ofT divaricata extract was added in 005M K2HPO4 and14mL hydrogen peroxide (H2O2) which was taken as asubstrate and catalase enzymes were added for the de-composition of H2O2)e decomposition was detected usinga UV spectrophotometer (UV-1601 Shimadzu Germany)by calculating the reduction in the absorbance for 5min at240 nm )e results of this activity are denoted as μM ofconsumed H2O2minmg of protein Similarly peroxidase(POD) activity was checked in which guaiacol was used ashydrogen )e experiment was carried out by measuring thedifference at 470 nm for 1 minute )e enzymatic activitywas described as a unit (one activity unit defined as ab-sorbance at 470 nm changes 0001 per min) [21] )e rate ofinhibition in the photoreduction of nitroblue tetrazolium(NBT) by the mean of superoxide dismutase (SOD) enzymeswas calculated to determine SOD operation )e reactionmixture used in this activity has 50mM sodium phosphatebuffer of pH 76 50mM sodium carbonate 01mM EDTA50 μM NBT 12mMmiddotL-methionine 10 μL riboflavin and100 μL crude extract within an exact having 30mL volumeOn the other hand the control reaction was preceded in theabsence of extract )e SOD behavior was measured byexposing the following reaction mixture to white light atroom temperature for 15 minutes After incubation for15min the absorbance was noted at 560 nm with the help ofa spectrophotometer [22]

23 Cytotoxicity through Hemolytic Activity To estimate thehemolytic activity of plant extract against human red bloodcells (RBCs) the method of Powell et al [23] was followedPBS was used as the negative control while 01 TritonX-100 was served as a positive control )e absorbance at576 nm was noted

2 Evidence-Based Complementary and Alternative Medicine

Hemolysis

Absorbance of sample minus Absorbance of negative control

Absorbance of positive control

times 100

(2)

24 Antidiabetic Assays

241 α-Amylase Inhibition Assay α-Amylase inhibitoryactivity of T divaricata flower extract was assessed by fol-lowing the procedure of Shai et al [24] Various concen-trations of extract were incubated in phosphate buffer of01molL at pH 68 and 2UmL porcine pancreatic amylase500 μL for 20minutes at 37degC 1 starch of 200 μL was mixedin phosphate buffer of 01molL with pH 68 and added tomixtures of extract After incubation at 37degC for 1 h 1mL ofcolor reagent (35dinitrosalicylic acid) was added to themixtures and finally the absorbance was recorded at 540 nmafter boiling this mixture for 10 minutes Control waswithout inhibitor and the percentage of inhibitory efficaciesof the extract was measured using the following formula

αminus amylaseinhibition() A540control minus A540sample

A540controltimes100

(3)

242 Intestinal α-Glucosidase Inhibitory Assay )e inhib-itory capability of α-glucosidase was evaluated by followingthe procedure of Ademiluyi and Oboh [25] with somemodifications Different concentrations of the extract weremixed with a 100 μl solution of 10UmL α-glucosidase andphosphate buffer whose pH was adjusted to 68 and themixtures were incubated for 15 minutes at 37degC After this5mmolL solutions of PNPG with the amount of 50 μL inphosphate buffer 01molL (pH 68) were poured into thesolutions and incubated again for 20 minutes at 37degC )eabsorbance of the control and sample was measured at405 nm and the percentage inhibitory activity of glucosidasewas calculated using the following formula

Percentage inhibition Acontrol minus Asample

Acontroltimes 100 (4)

where Acontrol is the absorbance of the mixture withoutextract and Asample is the absorbance of the mixture with theextract

243 Glucose Uptake in Yeast Cells )e protocol of Cirillo[26] was used to perform glucose uptake in yeast cellsSuspension of yeast (1) was centrifuged for 5min at4200 rpm By taking supernatant 10 vv yeast cells thesuspension was prepared 2mg of an extract was dissolved in1mL of DMSO )ese mixtures were then added in thedifferent molar concentrations of 1mL solution of glucose

and at 37degC incubated for 10min For starting the reaction100 μL of suspension was added to this mixture then vor-texed and incubated again at 37degC for 60min )e mixturewas then centrifuged at 3800 rpm for 5min and for theestimation of glucose the absorbance was taken at 520 nm)e percent increase in glucose uptake was calculated usingthe following formula

Increase in percentage of glucose uptake

Acontrol minus Asample

Acontroltimes 100

(5)

)e control consisted of all the reagents except plantextract and metronidazole was used as a standard drug

25 In Silico Study

251 SwissADME Analysis Fourteen important bioactivecompounds in the methanolic extract of T divaricataflowers were selected due to their bioactive potential towardsantitumor antibacterial and anti-inflammatory propertiesand to give better pharmacological activities [27ndash29] )esecompounds enlisted in Table 1 are subjected to a theoreticalin silico ADME prediction study using the Web tool Swis-sADME (httpwwwsibswiss) To predict suitable properties2D structural models of analyzed compounds were drawn inSDF format and transferred to the simplified molecular-inputline-entry system (SMILES) format )e SwissADME servertool was used to measure physicochemical properties of thecompounds such as molecular weight number of hydrogenbond acceptors number of hydrogen bond donors numberof rotatable bonds molar refractivity lipophilicity (ALogP)and topological polar surface area (TPSA) )e drug-likenessefficiency of the selected compounds was examined for first-round screening using Lipinski Ghose and Veber rules basedon their physicochemical properties [30ndash32] and then phar-macokinetics and medicinal properties were also examined

Drug-likeness bioavailability and pharmacokineticabilities are important parameters to predict the activepotential molecules for the purpose of drug development Inthe clinical trials many potent medicines fail in the drugdevelopment phase because of their weak abilities To ensurethat the bioactive compounds of Tabernaemontana divar-icata have drug-like characteristics all of the compounds inthis study were subjected to ADME and prediction exper-iments before molecular docking

252 Molecular Docking Analysis )e compounds thatwent through the filter were docked with the target proteinresulting in improved docking studies that predicted thepotential binding of inhibitor to the protein According tothe results of SwissADME 9 of 26 compounds were chosento describe the major compounds contained in the extracts)e three-dimensional structures of compounds and targetprotein were calculated using the Protein Data Bank (PDB)database GOLD version 530 and BIOVIA DiscoveryStudio were used to perform docking calculations (httpwww3dsbioviacom) for designing and visualization [33]

Evidence-Based Complementary and Alternative Medicine 3

Hemolysis

Absorbance of sample minus Absorbance of negative control

Absorbance of positive control

times 100

(2)

24 Antidiabetic Assays

241 α-Amylase Inhibition Assay α-Amylase inhibitoryactivity of T divaricata flower extract was assessed by fol-lowing the procedure of Shai et al [24] Various concen-trations of extract were incubated in phosphate buffer of01molL at pH 68 and 2UmL porcine pancreatic amylase500 μL for 20minutes at 37degC 1 starch of 200 μL was mixedin phosphate buffer of 01molL with pH 68 and added tomixtures of extract After incubation at 37degC for 1 h 1mL ofcolor reagent (35dinitrosalicylic acid) was added to themixtures and finally the absorbance was recorded at 540 nmafter boiling this mixture for 10 minutes Control waswithout inhibitor and the percentage of inhibitory efficaciesof the extract was measured using the following formula

αminus amylaseinhibition() A540control minus A540sample

A540controltimes100

(3)

242 Intestinal α-Glucosidase Inhibitory Assay )e inhib-itory capability of α-glucosidase was evaluated by followingthe procedure of Ademiluyi and Oboh [25] with somemodifications Different concentrations of the extract weremixed with a 100 μl solution of 10UmL α-glucosidase andphosphate buffer whose pH was adjusted to 68 and themixtures were incubated for 15 minutes at 37degC After this5mmolL solutions of PNPG with the amount of 50 μL inphosphate buffer 01molL (pH 68) were poured into thesolutions and incubated again for 20 minutes at 37degC )eabsorbance of the control and sample was measured at405 nm and the percentage inhibitory activity of glucosidasewas calculated using the following formula

Percentage inhibition Acontrol minus Asample

Acontroltimes 100 (4)

where Acontrol is the absorbance of the mixture withoutextract and Asample is the absorbance of the mixture with theextract

243 Glucose Uptake in Yeast Cells )e protocol of Cirillo[26] was used to perform glucose uptake in yeast cellsSuspension of yeast (1) was centrifuged for 5min at4200 rpm By taking supernatant 10 vv yeast cells thesuspension was prepared 2mg of an extract was dissolved in1mL of DMSO )ese mixtures were then added in thedifferent molar concentrations of 1mL solution of glucose

and at 37degC incubated for 10min For starting the reaction100 μL of suspension was added to this mixture then vor-texed and incubated again at 37degC for 60min )e mixturewas then centrifuged at 3800 rpm for 5min and for theestimation of glucose the absorbance was taken at 520 nm)e percent increase in glucose uptake was calculated usingthe following formula

Increase in percentage of glucose uptake

Acontrol minus Asample

Acontroltimes 100

(5)

)e control consisted of all the reagents except plantextract and metronidazole was used as a standard drug

25 In Silico Study

251 SwissADME Analysis Fourteen important bioactivecompounds in the methanolic extract of T divaricataflowers were selected due to their bioactive potential towardsantitumor antibacterial and anti-inflammatory propertiesand to give better pharmacological activities [27ndash29] )esecompounds enlisted in Table 1 are subjected to a theoreticalin silico ADME prediction study using the Web tool Swis-sADME (httpwwwsibswiss) To predict suitable properties2D structural models of analyzed compounds were drawn inSDF format and transferred to the simplified molecular-inputline-entry system (SMILES) format )e SwissADME servertool was used to measure physicochemical properties of thecompounds such as molecular weight number of hydrogenbond acceptors number of hydrogen bond donors numberof rotatable bonds molar refractivity lipophilicity (ALogP)and topological polar surface area (TPSA) )e drug-likenessefficiency of the selected compounds was examined for first-round screening using Lipinski Ghose and Veber rules basedon their physicochemical properties [30ndash32] and then phar-macokinetics and medicinal properties were also examined

Drug-likeness bioavailability and pharmacokineticabilities are important parameters to predict the activepotential molecules for the purpose of drug development Inthe clinical trials many potent medicines fail in the drugdevelopment phase because of their weak abilities To ensurethat the bioactive compounds of Tabernaemontana divar-icata have drug-like characteristics all of the compounds inthis study were subjected to ADME and prediction exper-iments before molecular docking

252 Molecular Docking Analysis )e compounds thatwent through the filter were docked with the target proteinresulting in improved docking studies that predicted thepotential binding of inhibitor to the protein According tothe results of SwissADME 9 of 26 compounds were chosento describe the major compounds contained in the extracts)e three-dimensional structures of compounds and targetprotein were calculated using the Protein Data Bank (PDB)database GOLD version 530 and BIOVIA DiscoveryStudio were used to perform docking calculations (httpwww3dsbioviacom) for designing and visualization [33]

Evidence-Based Complementary and Alternative Medicine 3

(1) Protein Preparation for Dockings For the moleculardocking studies of the synthesized compounds GOLDdocking software version 530 was used Protein Data Bankwas used to obtain the coordinated crystal structure of the5kzw protein (httpwwwrcsborgpdbhomehomedo)[34] and saved in PDB format Essential hydrogen atomswere added with the aid of GOLD GOLD score is a functionthat mimics a molecular mechanism and has been optimizedfor calculating ligand-binding positions [35] Affinity (grid)maps of 10 A and grid points with 075 A spacing weregenerated [36]

(2) Ligand and Energy Minimization For ligandrsquos energyminimization the ChemDraw Ultra 120 and Chem3D Prowere used )e ligand atoms were given the Gasteiger partialcharges Rotatable bonds were described by merging non-polar hydrogen atoms )e ligands were obtained fromPubChem (httpspubchemncbinlmnihgov) [37] GOLDtakes into account the degree of freedom in the binding sitethat corresponds to the reorientation of hydrogen bonds ofdonor and acceptor groups Despite accounting for a smallfraction of the total conformational space available thisdegree of freedom accounts for a significant difference inbinding energy values [38]

(3) Ligand-Protein Docking For predicting the binding af-finities of a variety of ligands molecular docking protocolsare commonly used [39] )e parameters of moleculardocking software were used to conduct the experiments(httpswwwccdccamacuk) )e Lamarckian genetic al-gorithm (LGA) and the Solis and Wets local search method

were used to simulate docking [40] )e initial positionsorientations and torsions of the ligand molecules werechosen at random Each docking experiment was dividedinto ten separate runs each of which was set to end after amaximum of 15 energy evaluations

26 Statistical Analysis )e experimental results wereperformed in triplicate and the data were expressed asmeanplusmn SE One-way analysis of variance (ANOVA) wasdone for statistical analysis of data employing SPSS version220 For statistical significance plt 005 was consideredUsing GOLD version 530 and BIOVIA Discovery studiovisualizer (httpwww3dsbioviacom) docking calculationswere carried out

3 Results

31 Phytochemical Assays )e estimated total phenoliccontent of T divaricata methanolic extract ranged from3562plusmn 531 to 6232plusmn 402 )e estimated total flavonoidcontent of T divaricata flower extract ranged from1395plusmn 133 to 2453plusmn 061 )e maximum quantity of totalphenol and flavonoid was 1mg while the minimum was31 μg as shown in Table 2

32 Antioxidant Activities Extract antioxidant activity wasmeasured in comparison with ascorbic acid )e measuredantioxidant potential ranges from 149plusmn 033 to 159plusmn 233while ascorbic acid was 115plusmn 058 to 6557plusmn 134 )eantioxidant potential of the extract was less than ascorbic

Table 1 Physicochemical properties of flower extract of T divaricate

Physicochemical properties

Compound Formula MW Heavyatom

AromHA Csp3 Rotatable

bond

H+bond

acceptor

H+bonddonor

Molarrefractivity TPSA

LipophilicityConseco log

PowDodecatriene C15H24 20435 gmol 15 0 047 7 0 0 7232 000 386Cyclohexanepropanoic acid C10H16O3 18423 gmol 13 0 080 4 3 0 4955 4337 213

D-Glucopyranoside C18H32O16 50444 gmol 34 0 100 8 16 11 10054 26868 minus064

Vitamin D3 C27H44O 38464 gmol 28 0 078 6 1 1 12504 2023 508Desulphosinigrin C10H17NO65 27931 gmol 18 0 070 5 7 5 6533 14804 085Lactose C12H44O11 34230 gmol 23 0 100 4 11 8 6812 18953 135n-Hexadecanoicacid C16H32O2 25642 gmol 18 0 094 14 2 1 8080 3730 385

Cyclopropanetetradecanoicacid

C26H50O2 39467 gmol 28 0 096 22 0 2 12627 2630 648

Octadecadienoicacid C18H32O2 28045 gmol 20 0 072 14 2 1 8946 3730 414

Phthalonitrile C21H14N2O 31035 gmol 24 18 005 3 3 0 9279 5681 303Octadecatrienoicacid C25H40O6 43658 gmol 31 0 064 21 6 0 12472 7890 497

Squalene C30H50 41072 gmol 30 0 060 15 0 0 14348 000 637Cholestan C28H48O 40058 gmol 29 0 093 5 1 1 12842 2043 502Vitamin Aaldehyde C20H28O 28444 gmol 21 0 045 5 1 0 9371 1707 396

4 Evidence-Based Complementary and Alternative Medicine

acid at maximum concentration however the potential wasimproved at lower concentration in comparison withascorbic acid as shown in Table 2

321 Enzymatic Antioxidant Activities Enzymatic antiox-idant activities by T divaricata such as catalase (CAT)superoxide dismutase (SOD) and peroxidase (POD) asshown in Table 3 were 399 127 and 2380Umg proteinrespectively )e free radical scavenging along with anincrease in physiological antioxidants (eg CAT SOD andPOD) was possibly due to the presence of the phyto-chemicals of this plant

33 Cytotoxicity through Hemolytic Activity Hemolytic ac-tivity of any compound is a sign of common cytotoxicitytowards normal healthy cells In this research the extractexhibited 10 cytotoxicity towards human erythrocytes asshown in Table 3 Such findings demonstrated that if me-dicinal formulations from this plant are used at low con-centrations the parameters of the RBC membrane will notchange Further research is essential on this medicinal edibleplant in the context of drug development and discovery

34 Antidiabetic Potential

341 α-Amylase and α-Glucosidase Inhibitory )e esti-mated α-amylase concentration range of T divaricata flowerextract was 1676plusmn 397 to 4181plusmn 375)e average values ofα-glucosidase inhibitory activity ranged from 1788plusmn 140 to359plusmn 124 )e inhibition potential of both enzymes wasmaximum at 200 ugmL and minimum at 50 ugmL asshown in Table 4

342 Glucose Uptake by Yeast Cells )e uptake of glucosewas evaluated by incubation of yeast cells in different molarconcentrations of glucose and T divaricata extract At 5 10and 25mM glucose concentrations with 1 2 and 3mgmLconcentration of T divaricata extract the results showedthat by rising the extract concentration the uptake of glucosepercentage was increased while it showed an inverse relationwith the glucose molar concentration as described in detailin Figure 1 which shows the maximum absorbance at 5mMof glucose and 3mgmL concentration of extract

35 In Silico SwissADME Analysis Due to weak drug-like-liness and pharmacokinetic characteristics many potentdrugs fail in clinical trials or later stages of drug discovery

All of the compounds in this sample were subjected to drug-likeness and ADME prediction tests before moleculardocking to ensure that they had drug-like characteristics

351 Physicochemical Properties A drugrsquos physicochemicalproperties have a significant effect on its metabolic destiny inthe body)e results from Table 1 showed that the molecularweight of all compounds met the criterion (which shouldbele 500 gmol) except D-glucopyranoside (MW 50444 gmol) in accordance with one of the criteria laid down in theLipinski rule of five Of all the studied compounds 17compounds had less than 10 rotatable bonds and others hadmore than 10 which is not acceptable Further the molarrefractivity of all compounds was within the acceptablerange (40 and 130) except squalene 1-heptatriacotanol andmethyl ester and these three compounds satisfy the criteriafor oral bioavailability

TPSA is another key parameter correlated with thedrugrsquos bioavailability High oral bioavailability for passivelyabsorbed compounds has TPSAlt 140 A2 Table 1 reveals thatall the selected compounds were found to be polar with TPSAvalues ranging from 000 A2 to 8048 A2 except D-gluco-pyranoside desulphosinigrin and lactose which had thehighest TPSA (gt140 A2) High solubility can facilitate com-plete absorption of the administered through oral adminis-tration while low solubility limits the drug absorption in thegastrointestinal tract [41] Table 1 shows that all of the tested26 compounds have good to moderate water solubility with alog S value between minus018 and minus56 which may promote goodoral adsorption

352 Pharmacokinetic Properties Interestingly except forthree compounds as shown in Table 5 all were observedwith high intestinal absorption and thus could penetratevery easily through the intestinal lining and be accessible tothe cell membrane To meet their molecular target drugsthat function in the central nervous system (CNS) need tomove through the blood-brain barrier (BBB) However for

Table 2 Phytochemical constituents and antioxidant activity of methanolic extract of T divaricate

Concentration of extract Total phenol (mgg) Total flavonoid (mgg) Inhibition by DPPH Inhibition by ascorbic acid1mg 6232plusmn 402 2453plusmn 061 159plusmn 233 6557plusmn 134500 μg 5511plusmn 674 2225plusmn 200 674plusmn 145 4334plusmn 314250 μg 4437plusmn 848 1782plusmn 142 423plusmn 033 751plusmn 208125 μg 4136plusmn 746 1503plusmn 106 250plusmn 033 250plusmn 03362 μg 3915plusmn 594 1472plusmn 155 288plusmn 057 173plusmn 05831 μg 3562plusmn 531 1395plusmn 133 149plusmn 033 115plusmn 058

Table 3 Different enzymatic activities and cytotoxicity of meth-anolic extract of T divaricata flower

Enzymatic assays (UmL protein)Cytotoxicity

CAT POD SODT divaricata 302plusmn 34 074plusmn 02 1587plusmn 05 10-Ve control 289plusmn 011 051plusmn 01 275plusmn 035 063Triton X mdash mdash mdash 96

Evidence-Based Complementary and Alternative Medicine 5

drug molecules with a peripheral target little to no BBBpermeation may be needed to prevent side effects on thecentral nervous system [42]

)e blood-brain barrier (BBB) permeation expresses therelative affinity of the drug for the blood or brain tissueTable 5 indicates that 15 compounds are estimated to haveno penetration of the blood-brain barrier and thus thechance of CNS side effects is expected to be absent P gly-coprotein (P-gp) plays a significant role in protecting thecentral nervous system from xenobiotics [43] )e predictedoutcome shows that only 9 of 26 compounds are P-gpsubstrates and do not cause phospholipidosis )e other 17compounds on the other hand are non-substrates of P-gpand are therefore required to induce phospholipidosis on thephenyl ring )e cytochrome P450 (CYP) superfamily iscritical in drug removal through metabolic biotransforma-tion [44] )e less skin permeant the molecule is the lowerthe log Kp (in cms) is It is found that log Kp measurementsof all the compounds evaluated are within the limits (minus80 tominus10) except D-glucopyranoside desulphosinigrin andlactose [45]

353 Lipophilicity and Drug-Likeness )e result of Table 6showed that the log P values of all the compounds exceptbenzene dicarboxylic acid methylnonadecane phthalic acid1-heptatriacotanol and cyclopropane tetradecanoic acid)e selected compounds were found to be within the limitsie between 07 and + 50 indicating that they should havestrong permeability and oral absorption Drug-likenessqualitatively tests a moleculersquos likelihood of being an oraldrug candidate for bioavailability [45]

354 Rule of Five by Lipinski As per Lipinskirsquos rule of five[31] the drug is likely to be produced as a prospective oral

drug if the applicant violates none or less than one of thefollowing four conditions )e Abbot bioavailability score(BAS) is a rule-based semi-quantitative score that relies on atotal charge TPSA and the Lipinski filter violation thatdistinguishes four compound groups All of the selectedmolecules have a bioavailability score of 055 except fortetrazole octadecadienoic acid n-hexadecanoic acid andlactose indicating a chance of becoming the oral drug can-didates [45]

In this investigation 17 of 26 of the selected compoundsdid not pass ADME screening leaving 9 candidate com-pounds for the molecular docking analysis (Table 6) thusdemonstrating the potential usefulness of the series for drug-like compound growth

355 Medicinal Chemistry Pan-assay interference com-pounds or promiscuous compounds (PAINS) are substanceswith substructures that display a false reaction irrespectiveof the protein receptor with biologically potent output [46]Table 6 shows that all of the compounds return no PAINSalert For all the candidates in the library the syntheticaccessibility (SA) scores were found to be less than 5 exceptfor the 6 compounds that had scores more than 5 as shownin Table 6 )e score of SA is normalized between 1 (easysynthesis) and 10 (very difficult synthesis) For most can-didates in the library the SA scores were found to be lessthan 5 and thus have strong synthesis feasibility

)e lead-like rule-based approach lets the medicinalchemist define the required molecule to start lead optimi-zation Interestingly Table 6 shows that 10 compounds of 26have one violation of lead-likeness and these molecules aretherefore considered appropriate for initiating lead opti-mization Furthermore as is evident from the radar de-pictions 8 compounds with two violations are also found tomeet the requirement for oral bioavailability

Table 4 Percentage inhibition of α-amylase and α-glucosidase of T divaricate

Extract concentration Inhibition of α-amylase Inhibition of α-glucosidase200 μgml 4181plusmn 375 359plusmn 124150 μgml 3578plusmn 412 3178plusmn 172100 μgml 261plusmn 401 2271plusmn 31150 μgml 1676plusmn 397 1788plusmn 140

0102030405060708090

3 mg 3 mg 3 mg 2mg 2mg 2mg 1mg 1mg 1mg25mM 10mM 5mM 25mM 10mM 5mM 25mM 10mM 5mM

abso

rban

ce at

520

nm

concentration of extract

Figure 1 Percentage of glucose uptake by yeast cells

6 Evidence-Based Complementary and Alternative Medicine

356 Bioavailability Radar )e drug-likeness of a moleculecan be quickly determined using the bioavailability radar)e pink-colored region is the required physiochemicalspace for oral bioavailability and the moleculersquos radar plotmust fall entirely into the field to be considered drug-like[47] )e SwissADME prediction output revealed that 9compounds had the optimal range of all six propertieswhich indicates that they have competent chemotherapeuticpotential (Figure 2)

357 Molecular Docking )e molecular docking techniqueis used to calculate ligand-binding affinities and energieswhich is essential in the structure-based drug design process3D protonation energy minimization and prediction of theactive site for ligands were used to prepare the protein formolecular docking with the parameters left at their defaults)en using GOLD version 530 software ligands weredocked with the target protein (5 kzw) In our study 9secondary metabolites from T divaricata (Jasmine) flowerwere docked with α-glucosidase protein (5 kzw) which is theimportant protein for the key regulatory enzymes that areimportant in the diabetes management To prevent sugar

digestion and postprandial hyperglycemia glucosidase adigestive enzyme involved in carbohydrate digestion mustbe inhibited Table 7 contains a list of the compounds whichare downloaded from PubChem (httpspubchemncbinlmnihgov)

Following the selection of these nine compounds basedon SwissADME findings ChemDraw Ultra 120 andChem3D Pro were used in GOLD docking for energyminimization of ligands )e coordinate crystal structure ofthe 5kzw protein was obtained from the Protein Data Bankand loaded into GOLD suite version 530 with a resolutionof 0 GOLD 530 version was used to screen various dockedcomplexes based on docking fitness and GOLD ratings )eGOLD program identified the most effective compound forinteracting with the receptor of 270 )e binding com-patibility ie docking score and fitness was used to test theresults )e best drug was selected with the highest bindingaffinity with the receptor molecule As the ligand moleculethe number of hydrogen bonds formed and the bond dis-tance between the active site and inhibited atomic coordi-nates were used to decide the final docked conformation forvarious chemicals )e GOLD docking scores for the phy-tochemicals are given in Table 8

Table 5 Pharmacokinetic properties of flower extract of T divaricate

Pharmacokinetics

Compound Giabsorption

BBBpermeant

P-gpsubstrate

CYP1A2inhibitor

CYP2C19inhibitor

CYP2C9inhibitor

CYP2D6inhibitor

CYP3A4inhibitor

LogKp (skinpermeation)

Dodecatriene low No No Yes No Yes No No minus327Cyclohexanepropanoic acid High Yes No No No No No No minus670

D-Glucopyranoside Low No Yes No No No No No minus1353Vitamin D3 Low No No No No Yes No No minus300Desulphosinigrin Low No Yes No No No No No minus891Lactose Low No Yes No No No No No minus1092n-Hexadecanoic acid High Yes No Yes No Yes No No minus277Cyclopropanetetradecanoic acid Low No Yes Yes No No No No minus075

Octadecadienoicacid High Yes No Yes No Yes No No minus305

Phthalonitrile High Yes No Yes Yes Yes No No minus473Octadecatrienoicacid High No Yes No Yes Yes No Yes minus465

Squalene Low No No No No No No No minus058Cholestan Low No No No No No No No minus225Vitamin A aldehyde High No No Yes No Yes No No minus3601-Heptatriacotanol Low No Yes No No No No No 355Methyl ester Low No Yes Yes No No No No minus331Acetaldehyde Low No Yes Yes No No No No minus6762-Phenylthiolane High Yes No Yes No No No No minus525Propanamide High No No No No No No No minus721Cyclopropane High No No No No No No No minus671Cyclohexene 3-ethenyl Low Yes No No No No No No minus478

N-Methylallylamine Low No No No No No No No minus642Tetrazole High No No No No No No No minus744Benzenedicarboxylic acid High No No No No No No No minus271

Methylnonadecane Low No No Yes No No No No minus038Phthalic acid Low No No No No No No Yes minus316

Evidence-Based Complementary and Alternative Medicine 7

drug molecules with a peripheral target little to no BBBpermeation may be needed to prevent side effects on thecentral nervous system [42]

)e blood-brain barrier (BBB) permeation expresses therelative affinity of the drug for the blood or brain tissueTable 5 indicates that 15 compounds are estimated to haveno penetration of the blood-brain barrier and thus thechance of CNS side effects is expected to be absent P gly-coprotein (P-gp) plays a significant role in protecting thecentral nervous system from xenobiotics [43] )e predictedoutcome shows that only 9 of 26 compounds are P-gpsubstrates and do not cause phospholipidosis )e other 17compounds on the other hand are non-substrates of P-gpand are therefore required to induce phospholipidosis on thephenyl ring )e cytochrome P450 (CYP) superfamily iscritical in drug removal through metabolic biotransforma-tion [44] )e less skin permeant the molecule is the lowerthe log Kp (in cms) is It is found that log Kp measurementsof all the compounds evaluated are within the limits (minus80 tominus10) except D-glucopyranoside desulphosinigrin andlactose [45]

353 Lipophilicity and Drug-Likeness )e result of Table 6showed that the log P values of all the compounds exceptbenzene dicarboxylic acid methylnonadecane phthalic acid1-heptatriacotanol and cyclopropane tetradecanoic acid)e selected compounds were found to be within the limitsie between 07 and + 50 indicating that they should havestrong permeability and oral absorption Drug-likenessqualitatively tests a moleculersquos likelihood of being an oraldrug candidate for bioavailability [45]

354 Rule of Five by Lipinski As per Lipinskirsquos rule of five[31] the drug is likely to be produced as a prospective oral

drug if the applicant violates none or less than one of thefollowing four conditions )e Abbot bioavailability score(BAS) is a rule-based semi-quantitative score that relies on atotal charge TPSA and the Lipinski filter violation thatdistinguishes four compound groups All of the selectedmolecules have a bioavailability score of 055 except fortetrazole octadecadienoic acid n-hexadecanoic acid andlactose indicating a chance of becoming the oral drug can-didates [45]

In this investigation 17 of 26 of the selected compoundsdid not pass ADME screening leaving 9 candidate com-pounds for the molecular docking analysis (Table 6) thusdemonstrating the potential usefulness of the series for drug-like compound growth

355 Medicinal Chemistry Pan-assay interference com-pounds or promiscuous compounds (PAINS) are substanceswith substructures that display a false reaction irrespectiveof the protein receptor with biologically potent output [46]Table 6 shows that all of the compounds return no PAINSalert For all the candidates in the library the syntheticaccessibility (SA) scores were found to be less than 5 exceptfor the 6 compounds that had scores more than 5 as shownin Table 6 )e score of SA is normalized between 1 (easysynthesis) and 10 (very difficult synthesis) For most can-didates in the library the SA scores were found to be lessthan 5 and thus have strong synthesis feasibility

)e lead-like rule-based approach lets the medicinalchemist define the required molecule to start lead optimi-zation Interestingly Table 6 shows that 10 compounds of 26have one violation of lead-likeness and these molecules aretherefore considered appropriate for initiating lead opti-mization Furthermore as is evident from the radar de-pictions 8 compounds with two violations are also found tomeet the requirement for oral bioavailability

Table 4 Percentage inhibition of α-amylase and α-glucosidase of T divaricate

Extract concentration Inhibition of α-amylase Inhibition of α-glucosidase200 μgml 4181plusmn 375 359plusmn 124150 μgml 3578plusmn 412 3178plusmn 172100 μgml 261plusmn 401 2271plusmn 31150 μgml 1676plusmn 397 1788plusmn 140

0102030405060708090

3 mg 3 mg 3 mg 2mg 2mg 2mg 1mg 1mg 1mg25mM 10mM 5mM 25mM 10mM 5mM 25mM 10mM 5mM

abso

rban

ce at

520

nm

concentration of extract

Figure 1 Percentage of glucose uptake by yeast cells

6 Evidence-Based Complementary and Alternative Medicine

356 Bioavailability Radar )e drug-likeness of a moleculecan be quickly determined using the bioavailability radar)e pink-colored region is the required physiochemicalspace for oral bioavailability and the moleculersquos radar plotmust fall entirely into the field to be considered drug-like[47] )e SwissADME prediction output revealed that 9compounds had the optimal range of all six propertieswhich indicates that they have competent chemotherapeuticpotential (Figure 2)

357 Molecular Docking )e molecular docking techniqueis used to calculate ligand-binding affinities and energieswhich is essential in the structure-based drug design process3D protonation energy minimization and prediction of theactive site for ligands were used to prepare the protein formolecular docking with the parameters left at their defaults)en using GOLD version 530 software ligands weredocked with the target protein (5 kzw) In our study 9secondary metabolites from T divaricata (Jasmine) flowerwere docked with α-glucosidase protein (5 kzw) which is theimportant protein for the key regulatory enzymes that areimportant in the diabetes management To prevent sugar

digestion and postprandial hyperglycemia glucosidase adigestive enzyme involved in carbohydrate digestion mustbe inhibited Table 7 contains a list of the compounds whichare downloaded from PubChem (httpspubchemncbinlmnihgov)

Following the selection of these nine compounds basedon SwissADME findings ChemDraw Ultra 120 andChem3D Pro were used in GOLD docking for energyminimization of ligands )e coordinate crystal structure ofthe 5kzw protein was obtained from the Protein Data Bankand loaded into GOLD suite version 530 with a resolutionof 0 GOLD 530 version was used to screen various dockedcomplexes based on docking fitness and GOLD ratings )eGOLD program identified the most effective compound forinteracting with the receptor of 270 )e binding com-patibility ie docking score and fitness was used to test theresults )e best drug was selected with the highest bindingaffinity with the receptor molecule As the ligand moleculethe number of hydrogen bonds formed and the bond dis-tance between the active site and inhibited atomic coordi-nates were used to decide the final docked conformation forvarious chemicals )e GOLD docking scores for the phy-tochemicals are given in Table 8

Table 5 Pharmacokinetic properties of flower extract of T divaricate

Pharmacokinetics

Compound Giabsorption

BBBpermeant

P-gpsubstrate

CYP1A2inhibitor

CYP2C19inhibitor

CYP2C9inhibitor

CYP2D6inhibitor

CYP3A4inhibitor

LogKp (skinpermeation)

Dodecatriene low No No Yes No Yes No No minus327Cyclohexanepropanoic acid High Yes No No No No No No minus670

D-Glucopyranoside Low No Yes No No No No No minus1353Vitamin D3 Low No No No No Yes No No minus300Desulphosinigrin Low No Yes No No No No No minus891Lactose Low No Yes No No No No No minus1092n-Hexadecanoic acid High Yes No Yes No Yes No No minus277Cyclopropanetetradecanoic acid Low No Yes Yes No No No No minus075

Octadecadienoicacid High Yes No Yes No Yes No No minus305

Phthalonitrile High Yes No Yes Yes Yes No No minus473Octadecatrienoicacid High No Yes No Yes Yes No Yes minus465

Squalene Low No No No No No No No minus058Cholestan Low No No No No No No No minus225Vitamin A aldehyde High No No Yes No Yes No No minus3601-Heptatriacotanol Low No Yes No No No No No 355Methyl ester Low No Yes Yes No No No No minus331Acetaldehyde Low No Yes Yes No No No No minus6762-Phenylthiolane High Yes No Yes No No No No minus525Propanamide High No No No No No No No minus721Cyclopropane High No No No No No No No minus671Cyclohexene 3-ethenyl Low Yes No No No No No No minus478

N-Methylallylamine Low No No No No No No No minus642Tetrazole High No No No No No No No minus744Benzenedicarboxylic acid High No No No No No No No minus271

Methylnonadecane Low No No Yes No No No No minus038Phthalic acid Low No No No No No No Yes minus316

Evidence-Based Complementary and Alternative Medicine 7

356 Bioavailability Radar )e drug-likeness of a moleculecan be quickly determined using the bioavailability radar)e pink-colored region is the required physiochemicalspace for oral bioavailability and the moleculersquos radar plotmust fall entirely into the field to be considered drug-like[47] )e SwissADME prediction output revealed that 9compounds had the optimal range of all six propertieswhich indicates that they have competent chemotherapeuticpotential (Figure 2)

357 Molecular Docking )e molecular docking techniqueis used to calculate ligand-binding affinities and energieswhich is essential in the structure-based drug design process3D protonation energy minimization and prediction of theactive site for ligands were used to prepare the protein formolecular docking with the parameters left at their defaults)en using GOLD version 530 software ligands weredocked with the target protein (5 kzw) In our study 9secondary metabolites from T divaricata (Jasmine) flowerwere docked with α-glucosidase protein (5 kzw) which is theimportant protein for the key regulatory enzymes that areimportant in the diabetes management To prevent sugar

digestion and postprandial hyperglycemia glucosidase adigestive enzyme involved in carbohydrate digestion mustbe inhibited Table 7 contains a list of the compounds whichare downloaded from PubChem (httpspubchemncbinlmnihgov)

Following the selection of these nine compounds basedon SwissADME findings ChemDraw Ultra 120 andChem3D Pro were used in GOLD docking for energyminimization of ligands )e coordinate crystal structure ofthe 5kzw protein was obtained from the Protein Data Bankand loaded into GOLD suite version 530 with a resolutionof 0 GOLD 530 version was used to screen various dockedcomplexes based on docking fitness and GOLD ratings )eGOLD program identified the most effective compound forinteracting with the receptor of 270 )e binding com-patibility ie docking score and fitness was used to test theresults )e best drug was selected with the highest bindingaffinity with the receptor molecule As the ligand moleculethe number of hydrogen bonds formed and the bond dis-tance between the active site and inhibited atomic coordi-nates were used to decide the final docked conformation forvarious chemicals )e GOLD docking scores for the phy-tochemicals are given in Table 8

Table 5 Pharmacokinetic properties of flower extract of T divaricate

Pharmacokinetics

Compound Giabsorption

BBBpermeant

P-gpsubstrate

CYP1A2inhibitor

CYP2C19inhibitor

CYP2C9inhibitor

CYP2D6inhibitor

CYP3A4inhibitor

LogKp (skinpermeation)

Dodecatriene low No No Yes No Yes No No minus327Cyclohexanepropanoic acid High Yes No No No No No No minus670

D-Glucopyranoside Low No Yes No No No No No minus1353Vitamin D3 Low No No No No Yes No No minus300Desulphosinigrin Low No Yes No No No No No minus891Lactose Low No Yes No No No No No minus1092n-Hexadecanoic acid High Yes No Yes No Yes No No minus277Cyclopropanetetradecanoic acid Low No Yes Yes No No No No minus075

Octadecadienoicacid High Yes No Yes No Yes No No minus305

Phthalonitrile High Yes No Yes Yes Yes No No minus473Octadecatrienoicacid High No Yes No Yes Yes No Yes minus465

Squalene Low No No No No No No No minus058Cholestan Low No No No No No No No minus225Vitamin A aldehyde High No No Yes No Yes No No minus3601-Heptatriacotanol Low No Yes No No No No No 355Methyl ester Low No Yes Yes No No No No minus331Acetaldehyde Low No Yes Yes No No No No minus6762-Phenylthiolane High Yes No Yes No No No No minus525Propanamide High No No No No No No No minus721Cyclopropane High No No No No No No No minus671Cyclohexene 3-ethenyl Low Yes No No No No No No minus478

N-Methylallylamine Low No No No No No No No minus642Tetrazole High No No No No No No No minus744Benzenedicarboxylic acid High No No No No No No No minus271

Methylnonadecane Low No No Yes No No No No minus038Phthalic acid Low No No No No No No Yes minus316

Evidence-Based Complementary and Alternative Medicine 7

Table 6 Drug-likeness and medicinal properties of flower extract of T divaricate

Drug-likeness Medicinal chemistry

Compound Lipinski Ghose Veber Egen Muegge Bioavailabilityscore PAINS Leadlikeness Synthetic

accessibility

Dodecatriene Yes1 violation Yes Yes Yes

No2

violation055 0 alert No

2 violation 342

Cyclohexanepropanoic acid

Yes0 violation Yes Yes Yes

No1

violation055 0 alert No

1 violation 220

D-Glucopyranoside No3 violation

No2

violation

No1

violation

No1

violation

No4

violation017 0 alert No

2 violation 623

Vitamin D3 No1 violation

No2

violationYes

No1

violation

No2

violation055 0 alert No

2 violation 602

Desulphosinigrin Yes0 violation

No1

violation

No1

violation

No1

violationYes 055 0 alert Yes 514

Lactose No2 violation

No1

violation

No1

violation

No1

violation

No4

violation017 0 alert Yes 541

n-Hexadecanoic acid Yes1 violation Yes

No1

violationYes

No1

violation085 0 alert No

2 violation 231

Cyclopropanetetradecanoic acid

Yes1 violation

No2

violation

No1

violation

No1

violation

No2

violation055 0 alert No

3 violation 430

Octadecadienoicacid

Yes1 violation

No1

violation

No1

violation

No1

violation

No1

violation085 0 alert No

2 violation 310

Phthalonitrile Yes0 violation Yes Yes Yes Yes 055 0 alert No

1 violation 273

Octadecatrienoic acid Yes0 violation

No2

violation

No1

violationYes

No2

violation055 0 alert No

3 violation 454

Squalene Yes1 violation

No3

violation

No1

violation

No1

violation

No2

violation055 0 alert No

3 violation 473

Cholestan Yes1 violation

No2

violationYes

No1

violation

No2

violation055 0 alert No

2violation 530

Vitamin A aldehyde Yes1 violation

No1

violationYes Yes

No2

violation055 0 alert No

1 violation 416

1-Heptatriacotanol No2 violation

No4

violation

No1

violation

No1

violation

No3

violation017 0 alert No

3 violation 487

Methyl ester Yes1 violation

No3

violationYes

No1

violation

No1

violation055 0 alert No

2 violation 604

Acetaldehyde Yes0 violation

No3

violationYes Yes

No3

violation055 0 alert No

1 violation 100

2-Phenylthiolane Yes0 violation Yes Yes Yes

No2

violation055 0 alert No

1 violation 241

Propanamide Yes0 violation

No3

violationYes Yes

No2

violation055 0 alert No

1 violation 100

8 Evidence-Based Complementary and Alternative Medicine

For each ligand each docking routine returned the topten rated docked poses Compounds having maximum li-gand-receptor binding energy and interactions with thereceptor (lt6 A bond lengths) were predicted to be mosteffective Cyclopropane tetradecanoic acid 2-octyl- methylester 4-(4-methyl-2-biphenylyloxy) phthalonitrile showedthe best interaction with α-glucosidase (PDB ID 5kzw)and the protein having Gold fitness (3928 3721) and GOLDdocking score is -751and -653 including forming a hy-drogen bondwith LEUA 777 ARGA 779 ASNA 780 THRA 782 VAL A 784 LEU A 777 ARG A 779 VAL A 784LEUA 815 SER A 848 TRP A 849 CYS A 850 and LEUA846 respectively )ese molecules showed exceptionally goodinteraction with α-glucosidase protein 1610-dodecatriene711-dimethyl-3-methylene 2-phenylthiolane and cyclo-hexane propanoic acid 3-oxo- methyl ester showedmoderatebinding affinity (3269 2914 and 2829 respectively) andGOLD docking score is -403 0205 and 093 respectivelyhaving the interaction of hydrogen bond with LEU A 777ARG A 779 VAL A 784 LEU A 777 ARG A 779 VAL A784 LEU A 846 ARG A 779 and VAL A 784 Compounds(N-methylallylamine propanamide and cyclohexene 3-ethenyl) had the least interaction in the range of 2000 1916and 2383 with docking scores of -016 -059 and 0141H-Tetrazol-5-amine compound showed least interactions withthe range of fitness of 1721 and docking score of 000

2D view of protein-ligand interactions from the bestposes produced by Discovery Studio showed that all mol-ecules exhibited the same binding mode as shown inFigure 3 ARG A 779 LEU A 777 and VAL A 784 are threeimportant interactions between these atoms and theresidues

4 Discussion

Ethnobotanicals are widely used for the treatment of diabeticand oxidative stress-related conditions [48] however it stillrequires rigorous scientific validation )e amount ofpostprandial blood glucose is the key factor that must becontrolled in T2D management [49] )e drug interventionoften has inexorable consequences mostly hypoglycemiagastrointestinal damage and weight gain [50] Severalstudies have verified the antihyperglycemic properties ofplant extracts and herbal formulations that could be used asantidiabetic tonics Herbal medications are often thoughtto have fewer adverse side effects than prescription drugs[51]

)e correlation was found between hypoglycemic eventsof medicinal plants to the presence of phenol and flavonoids[52] According to previous studies flavonoids have an an-tidiabetic property and are a source of glucose uptake in tissuewith relevance to oxidative stress during diabetic conditions[53] Antidiabetic activity is due to the co-adjuvant effect ofbioactive compounds present in T divaricata

Plants have a phenolic compound that shows antioxidantactivity to prevent tissue damage Rauter et al [53] reportedphenolic content as antioxidants in selected Nigerian me-dicinal plants such as A platyneuron and B nitida in whichthe value of phenolic content ranged from 8233plusmn 030 to1167plusmn 009mg GAEg while Agbo et al [54] reported thatthe phenolic content ranged from 9777plusmn 077mg GAEg Inour results T divaricate showed maximum phenolic contentof 6232plusmn 402 Flavonoid is another parameter that is used forthe determination of antioxidant activity in medicinal plantsIn this study the average range of flavonoid ranged from

Table 6 Continued

Drug-likeness Medicinal chemistry

Compound Lipinski Ghose Veber Egen Muegge Bioavailabilityscore PAINS Leadlikeness Synthetic

accessibility

Cyclopropane Yes0 violation

No3

violationYes Yes

No3

violation055 0 alert No

1 violation 100

Cyclohexene 3-ethenyl

Yes0 violation

No2

violationYes Yes

No2

violation055 0 alert No

1 violation 320

N-Methylallylamine Yes0violation

No3

violationYes Yes

No3

violation055 0 alert No

1 violation 102

Tetrazole Yes0 violation

No4

violationYes Yes

No2

violation056 0 alert No

1 violation 212

Benzene dicarboxylicacid

Yes1 violation

No1

violation

No1

violation

No1

violation

No2

violation055 0 alert No

3 violation 341

Methylnonadecane Yes1 violation

No1

violation

No1

violation

No1

violation

No3

violation055 0 alert No

2 violation 272

Phthalic acid Yes1 violation

No2

violation

No1

violation

No1

violation

No2

violation055 0 alert No

3 violation 365

Evidence-Based Complementary and Alternative Medicine 9

1395plusmn 133 to 2453plusmn 061 Agbo et al [54] reported flavo-noid values in M afzelii extract ie 367plusmn 000mg QEgwhile Saeed et al [55] reported the value of 596plusmn 15 formethanolic plant extract of T leptophylla

Previous research has shown that diabetic beta cellsproduce reactive oxygen species (ROS) which are coun-teracted by the overexpression of antioxidant enzymes suchas superoxide dismutase (SOD) catalase (CAT) and per-oxidase (POX) Antioxidants protect beta cells from oxi-dative damage by scavenging the free radicals produced thuspreventing diabetes from developing [27ndash29] In transgenicmice overexpression of SOD has been shown to prevent thedevelopment of diabetic complications Since oxidative stressis linked to the development of diabetic complications andinflammation this study aimed to assess Tabernaemontanadivaricatarsquos antioxidant activity

Biological properties such as the antioxidant propertyare considered as an estimation of the nutritional and

medicinal value of plants [56] )e antioxidant activity ofmethanolic extract of T divaricata flowers was estimated byDPPH assay DPPH is a neutral free radical that helps astable molecule to tolerate an electron or hydrogen radical)e ability of natural antioxidants to reduce the DPPH freeradical is assessed by a decrease in absorbance at 520 nm Incomparison with regular ascorbic acid the extract showedstrong scavenging activity )e lower the absorbance themore the scavenging operation there was As a result thebioactive compounds in this plant can serve as antioxidantsand aid in the treatment of a variety of diseases includingdiabetes Antioxidant properties of natural compounds aresaid to correlate with antidiabetic properties or vice versa Inthis study the given antioxidant activity of the T divaricataflower extract could be connected to their good amount ofTFC and TPC which function as metal chelators reductionagents hydrogen donors and singlet oxygen quenchers andfree radical scavenger [57]

LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(a)

LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(b)

LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(c)LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(d)

LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(e)

LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(f )LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(g)

LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(h)

LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(i)

Figure 2 Structures of bioavailability radar (a) 1610-dodecatriene 711-dimethyl-3-methylene (b) 2-phenylthiolane propanamide (c)phthalonitrile (d) cyclohexane propanoic acid (e) cyclopropane tetradecanoic acid (f ) N-methylallylamine (g) propanamide (h) 1H-tetrazol-5-amine and (i) cyclohexene 3-ethenyl

10 Evidence-Based Complementary and Alternative Medicine

Table 7 Nine selective compound properties of molecular formulaweight for docking

Name of the compound Molecular formula MW PubChem ID Structure

1610-Dodecatriene 711-dimethyl-3-methylene- (Z)- C15H24 204 5317319

H

Cyclohexane propanoic acid 3-oxo- methyl ester C10H16O3 184 538977 H3C

O

O

O

Cyclopropane tetradecanoic acid 2-octyl- methyl ester C26H50O2 394 552099 H

OO

H

4-(4-Methyl-2-biphenylyloxy) phthalonitrile C21H14N2O 310 628209

N

NC

C

O

2-Phenylthiolane C10H12S 16427 596288

OS

Propanamide C3H7NO 7309 6578NH2

H3C

O

Cyclohexene 3-ethenyl C8H12 10818 522623

H2C

N-Methylallylamine C4H10ClN 10758 18326499CH3H2C

NH

1H-Tetrazol-5-amine ltCH5N5O 10308 12211273 NH2NH

NN

N

Evidence-Based Complementary and Alternative Medicine 11

Toxicity is an important factor in the design of phar-maceutical drugs and an important starting point for he-molytic actions providing principal knowledge on theinteraction at the cellular level between biological entitiesand molecules Hemolytic activity of any compound is a signof common cytotoxicity towards normal healthy cells In thisresearch MEAE exhibited 10 cytotoxicity toward humanerythrocytes as shown in Table 3 Such findings demonstratethat if medicinal formulations from this plant are used at lowconcentrations parameters of the RBC membrane will notchange Reports on the toxic effects of A esculentus areinsufficient A previous study conducted with aqueous andmethanolic extracts of the A esculentus fruit confirmed thatthere were no deaths up to a dose of 2000mgkg (po) inSwiss mice (n 6) for 7 days and no signs of toxicity [58]which may be one of the significant issues for considering itas an important vegetable for human use Further research isessential on this medicinal edible plant in the context of drugdevelopment and discovery

Dietary phenols and flavonoids in accumulation totheir antioxidant effects have been noticed to exert anti-hyperglycemic effects by binding to the transporters of

glucose [49] and spirited digestive enzyme inhibition [59])e carbohydrate-digesting enzymes α-glucosidase andα-amylase digest dietary starch and produce glucoseresulting in surge of postprandial glucose So the inhibition ofα-glucosidase and α-amylase activities is one of the primaryapproaches to managing hyperglycemic T2D patients

T divaricata has antidiabetic activity according to al-pha-amylase inhibitory tests )e percentage inhibitoryactivity of plant methanolic extract against alpha-amylaseenzyme increased in a dose-dependent manner )e plantextract concentration of 50 gml showed a percentage in-hibition of 28 while 200 gml showed a percentage inhi-bition of 61 At a high concentration of 200 gml theextract inhibited the alpha-amylase enzyme by 50 As aresult of the current inhibitory studies it has been discoveredthat the T divaricata plant extract is successful in inhibitingthe alpha-amylase enzyme which helps to postpone thebreakdown of starch into glucose and thus maintain glucoselevels in diabetic patients Dastjerdi et al [48] observedα-amylase inhibition activity of some plant extracts of Teucrium species values ranged from 4159plusmn 064 to7707plusmn 049 at 156mgmL to 25mgmL )e α-amylase

Table 8 Docking interactions of different active compounds of T divaricate

Compound Goldscore

Gold bindingfitness RMSD Residue Hydrophobicity Pka Distance

2-phenylthiolane 0205 2914 7861

LEU777 38 476ARG779 minus45 12 384VAL784 42 492LEU846 38 509

4-(4-Methyl-2-biphenylyloxy) phthalonitrile minus653 3721 6918

LEU777 38 457ARG779 minus45 12 47ASN780 minus35 319THR782 minus07 234VAL784 42 508LEU846 38 220

Cyclohexanepropanoic acid 3-oxo- methyl ester minus093 2829 6543 ARG779 minus45 12 226VAL784 42 442

Cyclopropane tetradecanoic acid 2-octyl- methylester minus751 3928 6909

LEU777 38 532ARG779 minus45 12 461VAL784 42 502LEU815 38 508SER848 minus08 247TRP849 minus09 264CYS850 25 9 374

1610-Dodecatriene 711-dimethyl-3-methylene- minus403 3269 6703LEU777 38 513ARG779 minus45 12 499VAL784 42 388

N-Methylallylamine minus016 2000 6588

LEU777 38 408ARG779 minus45 12 370THR782 minus07 152VAL784 42 484

Propanamide minus059 1916 6542LEU777 38 220THR782 minus07 286VAL784 42 528

1H-Tetrazol-5-amine 000 1721 6678GLU750 minus35 43 259ARG779 minus45 12 185ASN780 minus35 274

Cyclohexene 3-ethenyl 014 2383 6450LEU777 38 497ARG779 minus45 12 389VAL784 42 435

12 Evidence-Based Complementary and Alternative Medicine

N-Methylallylamine

Interactions

Conventional Hydrogen Bond

Alkyl

Phthalonitrile

Interactions

Unfavorable Bump

Pi-Donor Hydrogen Bond

Alkyl

Pi-Alkyl

Cyclopropane tetradecanoic acid2-octyl- methyl ester

Interactions

Conventional Hydrogen Bond

Corbon Hydrogen Bond

Alkyl

1H-Tetrazol-5-amine

Interactions

Conventional Hydrogen Bond

Pi-Sigma

Pi-Alkyl

Cyclohexanepropanoic acid

Interactions

Conventional Hydrogen Bond

Alkyl

Cyclohexene 3-ethenyl

Interactions

Alkyl

(a)

Figure 3 Continued

Evidence-Based Complementary and Alternative Medicine 13

inhibitory activity of methanol plant extract is most likely bypolar compounds that should be investigated further byisolating pure active compounds

At 50ndash200 gml concentrations of T divaricata ex-tract the percentage inhibition increased in a dose-de-pendent manner For the highest and lowestconcentrations respectively the percentage inhibitionranged from 60 to 31 (Table 4) )us by inhibiting thealpha-glucosidase enzyme the extract of T divaricatawhich contains various natural bioactive compoundshelps to reduce the rate of carbohydrate digestionlowering blood glucose levels and maintaining diabeticconditions

Glucose uptake is one of the in vitro methods used toexplore the antihyperglycemic effect of different compounds[60] )e average values of glucose uptake by yeast cells inthis study were 1305plusmn 13 to 695plusmn 478 Shehzadi et al[60] reported the evaluation of antihyperglycemic activitythrough in vitro assays (02 to 263) at 2mgmL which wasbelow the current research values )e results indicated allused concentrations under examination are capable of in-creasing the utilization and uptake of glucose in yeast cells

)e in silico prediction of molecular physicochemicalparameters bioavailability and the pharmacokinetics havebecome more relevant for the investigation of productivepotential drug molecules from a drug discovery standpoint[47] )eoretical experiments play a critical role in presentingaccurate data in a timely and comfortable manner Many freeonline platforms have recently been established for fasterscreening reducing the time and expense of drug testing (noanimal testing) [46] SwissADME is a modern comprehensivemethod developed by the Swiss Institute of Bioinformatics(SIB) that allows drug candidates to have their absorptiondelivery metabolism and excretion (ADME) parametersestimated [45] At the outset of the drug development processADME properties which determine either the potentialdrugrsquos access to the target or its removal by the organism arethe required properties that must be evaluated for the drug tobe selected In silico experiments based on measured phys-icochemical requirements can be used to check these pa-rameters SwissADME also provides information ongastrointestinal absorption (GIA) and blood-brain barrier(BBB) permeability in humans From twenty-six selectedcompounds only eight compounds fulfilled the criteria of

1 6 10-Dodecatriene 7 11-dimethyl-3-methylene

Interactions

Alkyl

2-phenylthiolane Propanamide

Interactions

Alkyl

Pi-Alkyl

Propanamide

Interactions

Conventional Hydrogen Bond

Alkyl

(b)

Figure 3 In silico molecular docking results of interactions between 5kzw proteins with screened compounds as ligand

14 Evidence-Based Complementary and Alternative Medicine

drug-likeness parameters So all of these nine compoundswere further processed for molecular docking by GOLD

To predict the affinity and behavior of small moleculesand drug candidates computational molecular docking iscommonly used to predict the binding orientation to theirprotein targets [61] We used molecular docking to modelvarious bioactive compounds isolated from the Jasmineplant that is known to inhibit glucosidase Because of theirlow price and comparatively greater protection with a lowfrequency of severe gastrointestinal side effects plants orplant-based substances may be a suitable source of gluco-sidase inhibitors [62] Hydrogen bonds play a crucial role inthe structure and interaction of protein-protein or ligand-receptor complexes Hydrogen bonds are important in drugdesign to ensure that the drug is unique to the protein targetTo back up the findings of this research a molecular dockingstudy was performed (cyclopropane tetradecanoic acid 2-octyl- methyl ester 4-(4-methyl-2-biphenylyloxy) phtha-lonitrile) which showed excellent interaction with 5kzwprotein having Gold fitness (3928 3721) and GOLDdocking score of -751 and -653 including the formation ofhydrogen bond with amino acids residues (1610-dodeca-triene 711-dimethyl-3-methylene 2-phenylthiolane andcyclohexane propanoic acid 3-oxo- methyl ester) )esemolecules showed exceptionally good interaction withα-glucosidase protein and can be considered as potentialmolecules that may prove to be beneficial in antiviral activitythrough their direct action on new castle disease [63] )esecompounds showed moderate binding affinity of 32692914 and 2829 and GOLD docking scores of -403 0205and 093 respectively N-methylallylamine propanamidecyclohexene and 3-ethenyl have the least interaction in therange of 2000 1916 and 2383 and docking scores of -016-059 and 014 while 1H-tetrazol-5-amine compoundshowed the least affinity towards 5kzw binding site

5 Conclusion

Since diabetes mellitus is a global epidemic effective drugswith less or no toxicity must be developed and one such wayis the use of herbal medicines having no side effects )isstudy investigated the antidiabetic and antioxidant prop-erties of T divaricata extract and found promising inhibitorsof two carbohydrate-related enzymes T divaricata has richphenolic and flavonoid contents As a flavonoid it has greatantidiabetic potential and also causes active uptake of glu-cose )e methanolic extract of T divaricate has great po-tential for stimulation of α-amylase and α-glucosidase sothat it can be used to treat diabetes In silico docking studiesof phytoactive compounds from T divaricata have beenproven to have potential drug capabilities in terms of theirpharmacokinetic and drug-likeness )e molecular dockinganalysis described some compounds that inhibited thetargets related to diabetes mellitus and showed encouragingresults with prominent inhibitory activity )is study showsthat T divaricata extract which is rich in important bio-active compounds can be used for diabetes It is suggested tocarry out long-term research work to recognize and isolatethe active moieties responsible for antidiabetic property and

to understand the mechanisms involved in glucose-loweringproperties of the plant

Data Availability

Data are available from authors on reasonable demand

Conflicts of Interest

)e authors declare that there are no conflicts of interestregarding the publication of this study

Acknowledgments

)e facilities and support provided by the Department ofZoology Government College University Faisalabad arehighly acknowledged

References

[1] C D Deshmukh and A Jain ldquoDiabetes mellitus a reviewrdquoInternational Journal of Pure and Applied Biosciences vol 3pp 224ndash230 2015

[2] American Diabetes Association (ADA) ldquo5 Lifestyle man-agement Standards of medical care in diabetesmdash2019rdquo Di-abetes Care vol 42 no 1 pp S46ndashS60 2019

[3] A Meeinta C Rojwipaporn R Chanaporn et al ldquoDiabetesmellitus HbA1c and lung function do they are relatedrdquo Di-abetes amp its Complications vol 2 no 3 pp 1ndash6 2018

[4] U Yoon L L Kwok and A Magkidis ldquoEfficacy of lifestyleinterventions in reducing diabetes incidence in patients withimpaired glucose tolerance a systematic review of random-ized controlled trialsrdquo BMC Proceedings vol 6 pp P28ndashP142012

[5] S B Aynalem and A J Zeleke ldquoPrevalence of diabetesmellitus and its risk factors among individuals aged 15 yearsand above in Mizan-Aman town a cross sectional studyrdquoInternational Journal of Endocrinology vol 2018 Article ID9317987 7 pages 2018

[6] D R Whiting L Guariguata C Weil and J Shaw ldquoIDFdiabetes atlas global estimates of the prevalence of diabetesfor 2011 and 2030rdquo Diabetes Research and Clinical Practicevol 94 pp 311ndash321 2011

[7] P Agarwal and R Gupta ldquoAlpha-amylase inhibition can treatdiabetes mellitusrdquo Research Review Journal of Medical HealthScience vol 5 pp 1ndash8 2016

[8] H Kaneto N Katakami M Matsuhisa and T A MatsuokaldquoRole of reactive oxygen species in the progression of type 2diabetes and atherosclerosisrdquo Mediators of Inflammationvol 2010 Article ID 453892 11 pages 2010

[9] Z Sun and R Albert ldquoBoolean models of cellular signalingnetworksrdquo in Handbook of Systems BiologyElsevier Amster-dam Netherlands 2013

[10] M Nazıroglu ldquoNew molecular mechanisms on the activationof TRPM2 channels by oxidative stress and ADP-riboserdquoNeurochemical Research vol 32 pp 1990ndash2001 2007

[11] R Dringen ldquoOxidative and antioxidative potential of brainmicroglial cellsrdquo Antioxidants and Redox Signaling vol 7pp 1223ndash1233 2005

[12] T Zahidi A Lekchiri T Zahidi W Lekchiri and A BerrichialdquoExtraction and comparison of two new peroxidases fromleaves and roots of Brassica oleraceae var ramoserdquo Journal of

Evidence-Based Complementary and Alternative Medicine 15

Materials and Environmental Science vol 9 pp 1398ndash14042018

[13] D M Kasote S S Katyare M V Hegde and H BaeldquoSignificance of antioxidant potential of plants and its rele-vance to therapeutic applicationsrdquo International Journal ofBiological Sciences vol 11 pp 982ndash991 2015

[14] W Kooti M Farokhipour Z Asadzadeh D Ashtary-Larkyand M Asadi-Samani ldquo)e role of medicinal plants in thetreatment of diabetes a systematic reviewrdquo Electronic Phy-sician vol 8 no 1 pp 1832ndash1842 2016

[15] M S Aslam and M S Ahmad ldquoWorldwide importance ofmedicinal plants current and historical perspectivesrdquo RecentAdvances in Biology and Medicine vol 02 p 88 2016

[16] S Ponnusamy R Ravindran S Zinjarde S Bhargava andA R Kumar ldquoEvaluation of traditional Indian antidiabeticmedicinal plants for human pancreatic amylase inhibitoryeffect in vitrordquo Evidence-Based Complementary and Alter-native Medicine vol 2011 Article ID 515647 10 pages 2011

[17] P P Bijeshmon and S George ldquoAntimicrobial activity andpowder microscopy of the flowers of Tabernaemontanadivaricata Rrdquo BRrdquo Indo American Journal of PharmaceuticalResearch vol 4 pp 1601ndash1605 2014

[18] V L Singleton R Orthofer and R M Lamuela-RaventosldquoAnalysis of total phenols and other oxidation substrates andantioxidants by means of folin-ciocalteu reagentrdquoMethods inEnzymology vol 299 pp 152ndash178 1999

[19] J Bao Y Cai M Sun G Wang and H Corke ldquoAnthocy-anins flavonols and free radical scavenging activity of Chi-nese bayberry (Myrica rubra) extracts and their colorproperties and stabilityrdquo Journal of Agricultural and FoodChemistry vol 53 pp 2327ndash2332 2005

[20] M Mohebbi-Fani A Mirzaei S Nazifi and M R TabandehldquoOxidative status and antioxidant enzyme activities inerythrocytes from breeding and pregnant ewes grazing nat-ural pastures in dry seasonrdquo Revue de Medecine Veterinairevol 163 pp 454ndash460 2012

[21] G H Onsa N bin Saari J Selamat and J Bakar ldquoPurificationand characterization of membrane-bound peroxidases fromMetroxylon sagurdquo Food Chemistry vol 85 no 3 pp 365ndash3762004

[22] M Kumar A J Bijo R S Baghel C Reddy and B JhaldquoSelenium and spermine alleviate cadmium induced toxicityin the red seaweed Gracilaria dura by regulating antioxidantsand DNA methylationrdquo Plant Physiology and Biochemistryvol 51 pp 129ndash138 2012

[23] W A Powell C M Catranis and C A Maynard ldquoDesign ofself-processing antimicrobial peptides for plant protectionrdquoLetters in Applied Microbiology vol 31 pp 163ndash168 2000

[24] L J Shai P Masoko M P Mokgotho et al ldquoYeast alphaglucosidase inhibitory and antioxidant activities of six me-dicinal plants collected in Phalaborwa South Africardquo SouthAfrican Journal of Botany vol 76 pp 465ndash470 2010

[25] A O Ademiluyi and G Oboh ldquoSoybean phenolic-rich extractsinhibit key-enzymes linked to type 2 diabetes (α-amylase andα-glucosidase) and hypertension (angiotensin I convertingenzyme) in vitrordquo Experimental amp Toxicologic Pathologyvol 65 pp 305ndash309 2013

[26] V P Cirillo ldquoMechanism of glucose transport across the yeastcell membranerdquo Journal of Bacteriology vol 84 pp 485ndash4911962

[27] C Kalaimagal ldquoIdentification of bioactive compounds inflower of Tabernaemontana divaricata (l) using gas chro-matographyndashmass spectrometry analysisrdquo Asian Journal of

Pharmaceutical and Clinical Research vol 12 pp 129ndash1322019

[28] H H Rassem A Hamid Nour and R Mohamed YunusldquoAnalysis of bioactive compounds for Jasmine flower via Gaschromatography-mass spectrometry (GC-MS)rdquo MalaysianJournal of Fundamental and Applied Sciences vol 14 no 2pp 198ndash201 2018

[29] M S Ali Khan AMMat Jais and A Afreen ldquoAnalogous andantioxidant activity mediated gastroprotective action ofTabernaemontana divaricata (L) R Br flower methanolicextract against chemically induced gastric ulcers in ratsrdquoBioMed Research International vol 2013 Article ID 18547618 pages 2013

[30] D F Veber S R Johnson H Y Cheng B R SmithK W Ward and K D Kopple ldquoMolecular properties thatinfluence the oral bioavailability of drug candidatesrdquo Journalof Medicinal Chemistry vol 45 no 12 pp 2615ndash2623 2002

[31] C A Lipinski A Lombardo B W Dominy F Dominy andP J Feeney ldquoExperimental and computational approaches toestimate solubility and permeability in drug discovery anddevelopment settingsrdquo Advanced Drug Delivery Reviewsvol 46 pp 3ndash26 2001

[32] A K Ghose V N Viswanadhan and J J Wendoloski ldquoAknowledge-based approach in designing combinatorial ormedicinal chemistry libraries for drug discovery 1 A qualitativeand quantitative characterization of known drug databasesrdquoJournal of Combinatorial Chemistry vol 1 pp 55ndash68 1999

[33] Z Bikadi and E Hazai ldquoApplication of the PM6 semi-em-pirical method to modeling proteins enhances docking ac-curacy of AutoDockrdquo Journal of Cheminformatics vol 1p 15 2009

[34] S S Azam A Saroosh N Zaman and S Raza ldquoRole ofN-acetylserotonin O-methyltransferase in bipolar disordersand its dynamicsrdquo Journal of Molecular Liquids vol 182pp 25ndash31 2013

[35] O Trott and A J Olson ldquoAutoDockVina improving thespeed and accuracy of docking with a new scoring functionefficient optimization and multi-threadingrdquo Journal ofComputational Chemistry vol 31 pp 455ndash461 2010

[36] G M Morris D S Goodsell R S Halliday et al ldquoAutomateddocking using a Lamarckian genetic algorithm and an em-pirical binding free energy functionrdquo Journal of Computa-tional Chemistry vol 19 no 14 pp 1639ndash1662 1998

[37] T A Halgren ldquoCharacterization of MMFF94 MMFF94s andother widely available force fields for conformational energiesand for intermolecular-interaction energies and geometriesrdquoJournal of Computational Chemistry vol 20 1999

[38] C Y Chung H Y Chung W T Sung et al ldquoMoleculardocking for protein folding structure and drug-likenessprediction WSEAS conferencerdquo International Journal ofBiology and Biomedicine vol 1 pp 57ndash63 2005

[39] G Li H Zhou Y Jiang et al ldquoDesign and synthesis of 4-arylpiperidinyl amide and N-arylpiperdin-3-yl-cyclopropanecarboxamide derivatives as novel melatonin receptor ligandsrdquoBioorganic amp Medicinal Chemistry Letters vol 21 no 4pp 1236ndash1242 2011

[40] F J Solis and R J B Wets ldquoMinimization by random searchtechniquesrdquoMathematics of Operations Research vol 6 no 1pp 19ndash30 1981

[41] I A Alswaidan K Sooknah L Rhyman et al ldquo2 4-Ditel-lurouracil and its 5-fluoro derivative )eoretical investiga-tions of structural energetics and ADME parametersrdquoComputational Biology and Chemistry vol 68 pp 56ndash632017

16 Evidence-Based Complementary and Alternative Medicine

[42] M F Fromm ldquoP-glycoprotein a defense mechanism limitingoral bioavailability and CNS accumulation of drugsrdquo Inter-national Journal of Clinical Pharmacology amp Eerapeuticsvol 38 no 2 pp 69ndash74 2000

[43] G Szakacs A Varadi C Ozvegy Laczka and B Sarkadi ldquo)erole of ABC transporters in drug absorption distributionmetabolism excretion and toxicity (ADME-Tox)rdquo Drug Dis-covery Today vol 13 no 9-10 pp 379ndash393 2008

[44] B Testa and S D Kraemer ldquo)e biochemistry of drugmetabolism an introduction part 2 Redox reactions and theirenzymesrdquo ChemInform vol 38 no 23 pp 257ndash405 2007

[45] S Meeran V Baskar S Syed Tajudeen and T K ShabeerldquoDesign ADME profiling and molecular docking simulationof new isoniazid schiff base analogs as MtKasB InhibitorsrdquoAsian Journal of Chemistry and Pharmaceutical Science vol 6pp 20ndash34 2018

[46] J B Baell and G A Holloway ldquoNew substructure filters forremoval of pan assay interference compounds (PAINS) fromscreening libraries and for their exclusion in bioassaysrdquoJournal of Medicinal Chemistry vol 53 no 7 pp 2719ndash27402010

[47] T J Ritchie P Ertl and R Lewis ldquo)e graphical represen-tation of ADME-related molecule properties for medicinalchemistsrdquo Drug Discovery Today vol 16 no 1-2 pp 65ndash722011

[48] Z M Dastjerdi F Namjoyan and M E Azemi ldquoAlphaamylase inhibition activity of some plants extract of Teucriumspeciesrdquo European Journal of Biological Sciences vol 7pp 26ndash31 2015

[49] I M E Lacroix and E C Y Li-Chan ldquoOverview of foodproducts and dietary constituents with antidiabetic propertiesand their putative mechanisms of action a natural approachto complement pharmacotherapy in the management of di-abetesrdquo Molecular Nutrition amp Food Research vol 58 no 1pp 61ndash78 2014

[50] H V Rupasinghe S Sekhon-Loodu T Mantso andM I Panayiotidis ldquoPhytochemicals in regulating fatty acidβ-oxidation Potential underlying mechanisms and their in-volvement in obesity and weight lossrdquo Pharmacology ampEerapeutics vol 165 pp 153ndash163 2016

[51] M Qasim Z Abideen M Y Adnan et al ldquoAntioxidantproperties phenolic composition bioactive compounds andnutritive value of medicinal halophytes commonly used asherbal teasrdquo South African Journal of Botany vol 110pp 240ndash250 2017

[52] B Romano E Pagano V Montanaro A L FortunatoNMilic and F Borrelli ldquoNovel insights into the pharmacologyof flavonoidsrdquo Phytotherapy Research vol 27 pp 1588ndash15962013

[53] A P Rauter A Martins C Borges et al ldquoAntihyperglycaemicand protective effects of flavonoids on streptozotocinndashinduceddiabetic ratsrdquo Phytotherapy Research vol 24 pp S133ndashS1382010

[54] M O Agbo P F Uzor U N Nneji C U OdurukweU B Ogbatue and E C Mbaoji ldquoAntioxidant total phenolicand flavonoid content of selected Nigerian medicinal plantsrdquoDhaka University Journal of Pharmaceutical Science vol 14pp 35ndash41 2015

[55] N Saeed M R Khan and M Shabbir ldquoAntioxidant activitytotal phenolic and total flavonoid contents of whole plantextracts Torilis leptophylla Lrdquo BMC Complementary andAlternative Medicine vol 12 no 1 p 221 2012

[56] M R Kumbhare V Guleha and T Sivakumar ldquoEstimationof total phenolic content cytotoxicity and inndashvitro

antioxidant activity of stem bark of Moringa oleiferardquo AsianPacific Journal of Tropical Disease vol 2 pp 144ndash150 2012

[57] A A Ala B B Olotu and C M D Ohia ldquoAssessment ofcytotoxicity of leaf extracts of andrographis paniculata andaspilia Africana onmurine cellsrdquoArchives of basic and appliedmedicine vol 6 pp 61ndash65 2018

[58] S K Doreddula S R Bonam D P Gaddam B S R DesuN Ramarao and V Pandy ldquoPhytochemical analysis antioxi-dant antistress and nootropic activities of aqueous andmethanolic seed extracts of ladies finger (Abelmoschus escu-lentus L) in micerdquo Ee Scientific World Journal vol 2014Article ID 519848 14 pages 2014

[59] L A Nistor Baldea L C Martineau A Benhaddou-Anda-loussi J T Arnason E Levy and P S Haddad ldquoInhibition ofintestinal glucose absorption by anti-diabetic medicinal plantsderived from the James Bay Cree traditional pharmacopeiardquoJournal of Ethnopharmacology vol 132 no 2 pp 473ndash4822010

[60] N Shehzadi K Hussain N I Bukhari et al ldquoHypoglycemichepatoprotective and molecular docking studies of 5-[(4-chlorophenoxy) methyl]-1 3 4- oxadiazole-2-thiolrdquo Ban-gladesh Journal of Pharmacology vol 13 no 2 pp 149ndash1562018

[61] D Seeliger B L de Groot and V De Pymol ldquoLigand dockingand binding site analysis with PyMOL and AutodockVinardquoJournal of Computer-Aided Molecular Design vol 24pp 417ndash422 2010

[62] W Benalla S Bellahcen and M Bnouham ldquoAntidiabeticmedicinal plants as a source of alpha glucosidase inhibitorsrdquoCurrent Diabetes Reviews vol 6 no 4 pp 247ndash254 2010

[63] R Andleeb M U Ijaz A Rafique et al ldquoBiological activitiesof methanolic extract of aegle marmelos against HN protein ofnewcastle disease virusrdquo Agronomy vol 11 no 9 p 17842021

Evidence-Based Complementary and Alternative Medicine 17

For each ligand each docking routine returned the topten rated docked poses Compounds having maximum li-gand-receptor binding energy and interactions with thereceptor (lt6 A bond lengths) were predicted to be mosteffective Cyclopropane tetradecanoic acid 2-octyl- methylester 4-(4-methyl-2-biphenylyloxy) phthalonitrile showedthe best interaction with α-glucosidase (PDB ID 5kzw)and the protein having Gold fitness (3928 3721) and GOLDdocking score is -751and -653 including forming a hy-drogen bondwith LEUA 777 ARGA 779 ASNA 780 THRA 782 VAL A 784 LEU A 777 ARG A 779 VAL A 784LEUA 815 SER A 848 TRP A 849 CYS A 850 and LEUA846 respectively )ese molecules showed exceptionally goodinteraction with α-glucosidase protein 1610-dodecatriene711-dimethyl-3-methylene 2-phenylthiolane and cyclo-hexane propanoic acid 3-oxo- methyl ester showedmoderatebinding affinity (3269 2914 and 2829 respectively) andGOLD docking score is -403 0205 and 093 respectivelyhaving the interaction of hydrogen bond with LEU A 777ARG A 779 VAL A 784 LEU A 777 ARG A 779 VAL A784 LEU A 846 ARG A 779 and VAL A 784 Compounds(N-methylallylamine propanamide and cyclohexene 3-ethenyl) had the least interaction in the range of 2000 1916and 2383 with docking scores of -016 -059 and 0141H-Tetrazol-5-amine compound showed least interactions withthe range of fitness of 1721 and docking score of 000

2D view of protein-ligand interactions from the bestposes produced by Discovery Studio showed that all mol-ecules exhibited the same binding mode as shown inFigure 3 ARG A 779 LEU A 777 and VAL A 784 are threeimportant interactions between these atoms and theresidues

4 Discussion

Ethnobotanicals are widely used for the treatment of diabeticand oxidative stress-related conditions [48] however it stillrequires rigorous scientific validation )e amount ofpostprandial blood glucose is the key factor that must becontrolled in T2D management [49] )e drug interventionoften has inexorable consequences mostly hypoglycemiagastrointestinal damage and weight gain [50] Severalstudies have verified the antihyperglycemic properties ofplant extracts and herbal formulations that could be used asantidiabetic tonics Herbal medications are often thoughtto have fewer adverse side effects than prescription drugs[51]

)e correlation was found between hypoglycemic eventsof medicinal plants to the presence of phenol and flavonoids[52] According to previous studies flavonoids have an an-tidiabetic property and are a source of glucose uptake in tissuewith relevance to oxidative stress during diabetic conditions[53] Antidiabetic activity is due to the co-adjuvant effect ofbioactive compounds present in T divaricata

Plants have a phenolic compound that shows antioxidantactivity to prevent tissue damage Rauter et al [53] reportedphenolic content as antioxidants in selected Nigerian me-dicinal plants such as A platyneuron and B nitida in whichthe value of phenolic content ranged from 8233plusmn 030 to1167plusmn 009mg GAEg while Agbo et al [54] reported thatthe phenolic content ranged from 9777plusmn 077mg GAEg Inour results T divaricate showed maximum phenolic contentof 6232plusmn 402 Flavonoid is another parameter that is used forthe determination of antioxidant activity in medicinal plantsIn this study the average range of flavonoid ranged from

Table 6 Continued

Drug-likeness Medicinal chemistry

Compound Lipinski Ghose Veber Egen Muegge Bioavailabilityscore PAINS Leadlikeness Synthetic

accessibility

Cyclopropane Yes0 violation

No3

violationYes Yes

No3

violation055 0 alert No

1 violation 100

Cyclohexene 3-ethenyl

Yes0 violation

No2

violationYes Yes

No2

violation055 0 alert No

1 violation 320

N-Methylallylamine Yes0violation

No3

violationYes Yes

No3

violation055 0 alert No

1 violation 102

Tetrazole Yes0 violation

No4

violationYes Yes

No2

violation056 0 alert No

1 violation 212

Benzene dicarboxylicacid

Yes1 violation

No1

violation

No1

violation

No1

violation

No2

violation055 0 alert No

3 violation 341

Methylnonadecane Yes1 violation

No1

violation

No1

violation

No1

violation

No3

violation055 0 alert No

2 violation 272

Phthalic acid Yes1 violation

No2

violation

No1

violation

No1

violation

No2

violation055 0 alert No

3 violation 365

Evidence-Based Complementary and Alternative Medicine 9

1395plusmn 133 to 2453plusmn 061 Agbo et al [54] reported flavo-noid values in M afzelii extract ie 367plusmn 000mg QEgwhile Saeed et al [55] reported the value of 596plusmn 15 formethanolic plant extract of T leptophylla

Previous research has shown that diabetic beta cellsproduce reactive oxygen species (ROS) which are coun-teracted by the overexpression of antioxidant enzymes suchas superoxide dismutase (SOD) catalase (CAT) and per-oxidase (POX) Antioxidants protect beta cells from oxi-dative damage by scavenging the free radicals produced thuspreventing diabetes from developing [27ndash29] In transgenicmice overexpression of SOD has been shown to prevent thedevelopment of diabetic complications Since oxidative stressis linked to the development of diabetic complications andinflammation this study aimed to assess Tabernaemontanadivaricatarsquos antioxidant activity

Biological properties such as the antioxidant propertyare considered as an estimation of the nutritional and

medicinal value of plants [56] )e antioxidant activity ofmethanolic extract of T divaricata flowers was estimated byDPPH assay DPPH is a neutral free radical that helps astable molecule to tolerate an electron or hydrogen radical)e ability of natural antioxidants to reduce the DPPH freeradical is assessed by a decrease in absorbance at 520 nm Incomparison with regular ascorbic acid the extract showedstrong scavenging activity )e lower the absorbance themore the scavenging operation there was As a result thebioactive compounds in this plant can serve as antioxidantsand aid in the treatment of a variety of diseases includingdiabetes Antioxidant properties of natural compounds aresaid to correlate with antidiabetic properties or vice versa Inthis study the given antioxidant activity of the T divaricataflower extract could be connected to their good amount ofTFC and TPC which function as metal chelators reductionagents hydrogen donors and singlet oxygen quenchers andfree radical scavenger [57]

LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(a)

LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(b)

LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(c)LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(d)

LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(e)

LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(f )LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(g)

LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(h)

LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(i)

Figure 2 Structures of bioavailability radar (a) 1610-dodecatriene 711-dimethyl-3-methylene (b) 2-phenylthiolane propanamide (c)phthalonitrile (d) cyclohexane propanoic acid (e) cyclopropane tetradecanoic acid (f ) N-methylallylamine (g) propanamide (h) 1H-tetrazol-5-amine and (i) cyclohexene 3-ethenyl

10 Evidence-Based Complementary and Alternative Medicine

Table 7 Nine selective compound properties of molecular formulaweight for docking

Name of the compound Molecular formula MW PubChem ID Structure

1610-Dodecatriene 711-dimethyl-3-methylene- (Z)- C15H24 204 5317319

H

Cyclohexane propanoic acid 3-oxo- methyl ester C10H16O3 184 538977 H3C

O

O

O

Cyclopropane tetradecanoic acid 2-octyl- methyl ester C26H50O2 394 552099 H

OO

H

4-(4-Methyl-2-biphenylyloxy) phthalonitrile C21H14N2O 310 628209

N

NC

C

O

2-Phenylthiolane C10H12S 16427 596288

OS

Propanamide C3H7NO 7309 6578NH2

H3C

O

Cyclohexene 3-ethenyl C8H12 10818 522623

H2C

N-Methylallylamine C4H10ClN 10758 18326499CH3H2C

NH

1H-Tetrazol-5-amine ltCH5N5O 10308 12211273 NH2NH

NN

N

Evidence-Based Complementary and Alternative Medicine 11

Toxicity is an important factor in the design of phar-maceutical drugs and an important starting point for he-molytic actions providing principal knowledge on theinteraction at the cellular level between biological entitiesand molecules Hemolytic activity of any compound is a signof common cytotoxicity towards normal healthy cells In thisresearch MEAE exhibited 10 cytotoxicity toward humanerythrocytes as shown in Table 3 Such findings demonstratethat if medicinal formulations from this plant are used at lowconcentrations parameters of the RBC membrane will notchange Reports on the toxic effects of A esculentus areinsufficient A previous study conducted with aqueous andmethanolic extracts of the A esculentus fruit confirmed thatthere were no deaths up to a dose of 2000mgkg (po) inSwiss mice (n 6) for 7 days and no signs of toxicity [58]which may be one of the significant issues for considering itas an important vegetable for human use Further research isessential on this medicinal edible plant in the context of drugdevelopment and discovery

Dietary phenols and flavonoids in accumulation totheir antioxidant effects have been noticed to exert anti-hyperglycemic effects by binding to the transporters of

glucose [49] and spirited digestive enzyme inhibition [59])e carbohydrate-digesting enzymes α-glucosidase andα-amylase digest dietary starch and produce glucoseresulting in surge of postprandial glucose So the inhibition ofα-glucosidase and α-amylase activities is one of the primaryapproaches to managing hyperglycemic T2D patients

T divaricata has antidiabetic activity according to al-pha-amylase inhibitory tests )e percentage inhibitoryactivity of plant methanolic extract against alpha-amylaseenzyme increased in a dose-dependent manner )e plantextract concentration of 50 gml showed a percentage in-hibition of 28 while 200 gml showed a percentage inhi-bition of 61 At a high concentration of 200 gml theextract inhibited the alpha-amylase enzyme by 50 As aresult of the current inhibitory studies it has been discoveredthat the T divaricata plant extract is successful in inhibitingthe alpha-amylase enzyme which helps to postpone thebreakdown of starch into glucose and thus maintain glucoselevels in diabetic patients Dastjerdi et al [48] observedα-amylase inhibition activity of some plant extracts of Teucrium species values ranged from 4159plusmn 064 to7707plusmn 049 at 156mgmL to 25mgmL )e α-amylase

Table 8 Docking interactions of different active compounds of T divaricate

Compound Goldscore

Gold bindingfitness RMSD Residue Hydrophobicity Pka Distance

2-phenylthiolane 0205 2914 7861

LEU777 38 476ARG779 minus45 12 384VAL784 42 492LEU846 38 509

4-(4-Methyl-2-biphenylyloxy) phthalonitrile minus653 3721 6918

LEU777 38 457ARG779 minus45 12 47ASN780 minus35 319THR782 minus07 234VAL784 42 508LEU846 38 220

Cyclohexanepropanoic acid 3-oxo- methyl ester minus093 2829 6543 ARG779 minus45 12 226VAL784 42 442

Cyclopropane tetradecanoic acid 2-octyl- methylester minus751 3928 6909

LEU777 38 532ARG779 minus45 12 461VAL784 42 502LEU815 38 508SER848 minus08 247TRP849 minus09 264CYS850 25 9 374

1610-Dodecatriene 711-dimethyl-3-methylene- minus403 3269 6703LEU777 38 513ARG779 minus45 12 499VAL784 42 388

N-Methylallylamine minus016 2000 6588

LEU777 38 408ARG779 minus45 12 370THR782 minus07 152VAL784 42 484

Propanamide minus059 1916 6542LEU777 38 220THR782 minus07 286VAL784 42 528

1H-Tetrazol-5-amine 000 1721 6678GLU750 minus35 43 259ARG779 minus45 12 185ASN780 minus35 274

Cyclohexene 3-ethenyl 014 2383 6450LEU777 38 497ARG779 minus45 12 389VAL784 42 435

12 Evidence-Based Complementary and Alternative Medicine

N-Methylallylamine

Interactions

Conventional Hydrogen Bond

Alkyl

Phthalonitrile

Interactions

Unfavorable Bump

Pi-Donor Hydrogen Bond

Alkyl

Pi-Alkyl

Cyclopropane tetradecanoic acid2-octyl- methyl ester

Interactions

Conventional Hydrogen Bond

Corbon Hydrogen Bond

Alkyl

1H-Tetrazol-5-amine

Interactions

Conventional Hydrogen Bond

Pi-Sigma

Pi-Alkyl

Cyclohexanepropanoic acid

Interactions

Conventional Hydrogen Bond

Alkyl

Cyclohexene 3-ethenyl

Interactions

Alkyl

(a)

Figure 3 Continued

Evidence-Based Complementary and Alternative Medicine 13

inhibitory activity of methanol plant extract is most likely bypolar compounds that should be investigated further byisolating pure active compounds

At 50ndash200 gml concentrations of T divaricata ex-tract the percentage inhibition increased in a dose-de-pendent manner For the highest and lowestconcentrations respectively the percentage inhibitionranged from 60 to 31 (Table 4) )us by inhibiting thealpha-glucosidase enzyme the extract of T divaricatawhich contains various natural bioactive compoundshelps to reduce the rate of carbohydrate digestionlowering blood glucose levels and maintaining diabeticconditions

Glucose uptake is one of the in vitro methods used toexplore the antihyperglycemic effect of different compounds[60] )e average values of glucose uptake by yeast cells inthis study were 1305plusmn 13 to 695plusmn 478 Shehzadi et al[60] reported the evaluation of antihyperglycemic activitythrough in vitro assays (02 to 263) at 2mgmL which wasbelow the current research values )e results indicated allused concentrations under examination are capable of in-creasing the utilization and uptake of glucose in yeast cells

)e in silico prediction of molecular physicochemicalparameters bioavailability and the pharmacokinetics havebecome more relevant for the investigation of productivepotential drug molecules from a drug discovery standpoint[47] )eoretical experiments play a critical role in presentingaccurate data in a timely and comfortable manner Many freeonline platforms have recently been established for fasterscreening reducing the time and expense of drug testing (noanimal testing) [46] SwissADME is a modern comprehensivemethod developed by the Swiss Institute of Bioinformatics(SIB) that allows drug candidates to have their absorptiondelivery metabolism and excretion (ADME) parametersestimated [45] At the outset of the drug development processADME properties which determine either the potentialdrugrsquos access to the target or its removal by the organism arethe required properties that must be evaluated for the drug tobe selected In silico experiments based on measured phys-icochemical requirements can be used to check these pa-rameters SwissADME also provides information ongastrointestinal absorption (GIA) and blood-brain barrier(BBB) permeability in humans From twenty-six selectedcompounds only eight compounds fulfilled the criteria of

1 6 10-Dodecatriene 7 11-dimethyl-3-methylene

Interactions

Alkyl

2-phenylthiolane Propanamide

Interactions

Alkyl

Pi-Alkyl

Propanamide

Interactions

Conventional Hydrogen Bond

Alkyl

(b)

Figure 3 In silico molecular docking results of interactions between 5kzw proteins with screened compounds as ligand

14 Evidence-Based Complementary and Alternative Medicine

drug-likeness parameters So all of these nine compoundswere further processed for molecular docking by GOLD

To predict the affinity and behavior of small moleculesand drug candidates computational molecular docking iscommonly used to predict the binding orientation to theirprotein targets [61] We used molecular docking to modelvarious bioactive compounds isolated from the Jasmineplant that is known to inhibit glucosidase Because of theirlow price and comparatively greater protection with a lowfrequency of severe gastrointestinal side effects plants orplant-based substances may be a suitable source of gluco-sidase inhibitors [62] Hydrogen bonds play a crucial role inthe structure and interaction of protein-protein or ligand-receptor complexes Hydrogen bonds are important in drugdesign to ensure that the drug is unique to the protein targetTo back up the findings of this research a molecular dockingstudy was performed (cyclopropane tetradecanoic acid 2-octyl- methyl ester 4-(4-methyl-2-biphenylyloxy) phtha-lonitrile) which showed excellent interaction with 5kzwprotein having Gold fitness (3928 3721) and GOLDdocking score of -751 and -653 including the formation ofhydrogen bond with amino acids residues (1610-dodeca-triene 711-dimethyl-3-methylene 2-phenylthiolane andcyclohexane propanoic acid 3-oxo- methyl ester) )esemolecules showed exceptionally good interaction withα-glucosidase protein and can be considered as potentialmolecules that may prove to be beneficial in antiviral activitythrough their direct action on new castle disease [63] )esecompounds showed moderate binding affinity of 32692914 and 2829 and GOLD docking scores of -403 0205and 093 respectively N-methylallylamine propanamidecyclohexene and 3-ethenyl have the least interaction in therange of 2000 1916 and 2383 and docking scores of -016-059 and 014 while 1H-tetrazol-5-amine compoundshowed the least affinity towards 5kzw binding site

5 Conclusion

Since diabetes mellitus is a global epidemic effective drugswith less or no toxicity must be developed and one such wayis the use of herbal medicines having no side effects )isstudy investigated the antidiabetic and antioxidant prop-erties of T divaricata extract and found promising inhibitorsof two carbohydrate-related enzymes T divaricata has richphenolic and flavonoid contents As a flavonoid it has greatantidiabetic potential and also causes active uptake of glu-cose )e methanolic extract of T divaricate has great po-tential for stimulation of α-amylase and α-glucosidase sothat it can be used to treat diabetes In silico docking studiesof phytoactive compounds from T divaricata have beenproven to have potential drug capabilities in terms of theirpharmacokinetic and drug-likeness )e molecular dockinganalysis described some compounds that inhibited thetargets related to diabetes mellitus and showed encouragingresults with prominent inhibitory activity )is study showsthat T divaricata extract which is rich in important bio-active compounds can be used for diabetes It is suggested tocarry out long-term research work to recognize and isolatethe active moieties responsible for antidiabetic property and

to understand the mechanisms involved in glucose-loweringproperties of the plant

Data Availability

Data are available from authors on reasonable demand

Conflicts of Interest

)e authors declare that there are no conflicts of interestregarding the publication of this study

Acknowledgments

)e facilities and support provided by the Department ofZoology Government College University Faisalabad arehighly acknowledged

References

[1] C D Deshmukh and A Jain ldquoDiabetes mellitus a reviewrdquoInternational Journal of Pure and Applied Biosciences vol 3pp 224ndash230 2015

[2] American Diabetes Association (ADA) ldquo5 Lifestyle man-agement Standards of medical care in diabetesmdash2019rdquo Di-abetes Care vol 42 no 1 pp S46ndashS60 2019

[3] A Meeinta C Rojwipaporn R Chanaporn et al ldquoDiabetesmellitus HbA1c and lung function do they are relatedrdquo Di-abetes amp its Complications vol 2 no 3 pp 1ndash6 2018

[4] U Yoon L L Kwok and A Magkidis ldquoEfficacy of lifestyleinterventions in reducing diabetes incidence in patients withimpaired glucose tolerance a systematic review of random-ized controlled trialsrdquo BMC Proceedings vol 6 pp P28ndashP142012

[5] S B Aynalem and A J Zeleke ldquoPrevalence of diabetesmellitus and its risk factors among individuals aged 15 yearsand above in Mizan-Aman town a cross sectional studyrdquoInternational Journal of Endocrinology vol 2018 Article ID9317987 7 pages 2018

[6] D R Whiting L Guariguata C Weil and J Shaw ldquoIDFdiabetes atlas global estimates of the prevalence of diabetesfor 2011 and 2030rdquo Diabetes Research and Clinical Practicevol 94 pp 311ndash321 2011

[7] P Agarwal and R Gupta ldquoAlpha-amylase inhibition can treatdiabetes mellitusrdquo Research Review Journal of Medical HealthScience vol 5 pp 1ndash8 2016

[8] H Kaneto N Katakami M Matsuhisa and T A MatsuokaldquoRole of reactive oxygen species in the progression of type 2diabetes and atherosclerosisrdquo Mediators of Inflammationvol 2010 Article ID 453892 11 pages 2010

[9] Z Sun and R Albert ldquoBoolean models of cellular signalingnetworksrdquo in Handbook of Systems BiologyElsevier Amster-dam Netherlands 2013

[10] M Nazıroglu ldquoNew molecular mechanisms on the activationof TRPM2 channels by oxidative stress and ADP-riboserdquoNeurochemical Research vol 32 pp 1990ndash2001 2007

[11] R Dringen ldquoOxidative and antioxidative potential of brainmicroglial cellsrdquo Antioxidants and Redox Signaling vol 7pp 1223ndash1233 2005

[12] T Zahidi A Lekchiri T Zahidi W Lekchiri and A BerrichialdquoExtraction and comparison of two new peroxidases fromleaves and roots of Brassica oleraceae var ramoserdquo Journal of

Evidence-Based Complementary and Alternative Medicine 15

Materials and Environmental Science vol 9 pp 1398ndash14042018

[13] D M Kasote S S Katyare M V Hegde and H BaeldquoSignificance of antioxidant potential of plants and its rele-vance to therapeutic applicationsrdquo International Journal ofBiological Sciences vol 11 pp 982ndash991 2015

[14] W Kooti M Farokhipour Z Asadzadeh D Ashtary-Larkyand M Asadi-Samani ldquo)e role of medicinal plants in thetreatment of diabetes a systematic reviewrdquo Electronic Phy-sician vol 8 no 1 pp 1832ndash1842 2016

[15] M S Aslam and M S Ahmad ldquoWorldwide importance ofmedicinal plants current and historical perspectivesrdquo RecentAdvances in Biology and Medicine vol 02 p 88 2016

[16] S Ponnusamy R Ravindran S Zinjarde S Bhargava andA R Kumar ldquoEvaluation of traditional Indian antidiabeticmedicinal plants for human pancreatic amylase inhibitoryeffect in vitrordquo Evidence-Based Complementary and Alter-native Medicine vol 2011 Article ID 515647 10 pages 2011

[17] P P Bijeshmon and S George ldquoAntimicrobial activity andpowder microscopy of the flowers of Tabernaemontanadivaricata Rrdquo BRrdquo Indo American Journal of PharmaceuticalResearch vol 4 pp 1601ndash1605 2014

[18] V L Singleton R Orthofer and R M Lamuela-RaventosldquoAnalysis of total phenols and other oxidation substrates andantioxidants by means of folin-ciocalteu reagentrdquoMethods inEnzymology vol 299 pp 152ndash178 1999

[19] J Bao Y Cai M Sun G Wang and H Corke ldquoAnthocy-anins flavonols and free radical scavenging activity of Chi-nese bayberry (Myrica rubra) extracts and their colorproperties and stabilityrdquo Journal of Agricultural and FoodChemistry vol 53 pp 2327ndash2332 2005

[20] M Mohebbi-Fani A Mirzaei S Nazifi and M R TabandehldquoOxidative status and antioxidant enzyme activities inerythrocytes from breeding and pregnant ewes grazing nat-ural pastures in dry seasonrdquo Revue de Medecine Veterinairevol 163 pp 454ndash460 2012

[21] G H Onsa N bin Saari J Selamat and J Bakar ldquoPurificationand characterization of membrane-bound peroxidases fromMetroxylon sagurdquo Food Chemistry vol 85 no 3 pp 365ndash3762004

[22] M Kumar A J Bijo R S Baghel C Reddy and B JhaldquoSelenium and spermine alleviate cadmium induced toxicityin the red seaweed Gracilaria dura by regulating antioxidantsand DNA methylationrdquo Plant Physiology and Biochemistryvol 51 pp 129ndash138 2012

[23] W A Powell C M Catranis and C A Maynard ldquoDesign ofself-processing antimicrobial peptides for plant protectionrdquoLetters in Applied Microbiology vol 31 pp 163ndash168 2000

[24] L J Shai P Masoko M P Mokgotho et al ldquoYeast alphaglucosidase inhibitory and antioxidant activities of six me-dicinal plants collected in Phalaborwa South Africardquo SouthAfrican Journal of Botany vol 76 pp 465ndash470 2010

[25] A O Ademiluyi and G Oboh ldquoSoybean phenolic-rich extractsinhibit key-enzymes linked to type 2 diabetes (α-amylase andα-glucosidase) and hypertension (angiotensin I convertingenzyme) in vitrordquo Experimental amp Toxicologic Pathologyvol 65 pp 305ndash309 2013

[26] V P Cirillo ldquoMechanism of glucose transport across the yeastcell membranerdquo Journal of Bacteriology vol 84 pp 485ndash4911962

[27] C Kalaimagal ldquoIdentification of bioactive compounds inflower of Tabernaemontana divaricata (l) using gas chro-matographyndashmass spectrometry analysisrdquo Asian Journal of

Pharmaceutical and Clinical Research vol 12 pp 129ndash1322019

[28] H H Rassem A Hamid Nour and R Mohamed YunusldquoAnalysis of bioactive compounds for Jasmine flower via Gaschromatography-mass spectrometry (GC-MS)rdquo MalaysianJournal of Fundamental and Applied Sciences vol 14 no 2pp 198ndash201 2018

[29] M S Ali Khan AMMat Jais and A Afreen ldquoAnalogous andantioxidant activity mediated gastroprotective action ofTabernaemontana divaricata (L) R Br flower methanolicextract against chemically induced gastric ulcers in ratsrdquoBioMed Research International vol 2013 Article ID 18547618 pages 2013

[30] D F Veber S R Johnson H Y Cheng B R SmithK W Ward and K D Kopple ldquoMolecular properties thatinfluence the oral bioavailability of drug candidatesrdquo Journalof Medicinal Chemistry vol 45 no 12 pp 2615ndash2623 2002

[31] C A Lipinski A Lombardo B W Dominy F Dominy andP J Feeney ldquoExperimental and computational approaches toestimate solubility and permeability in drug discovery anddevelopment settingsrdquo Advanced Drug Delivery Reviewsvol 46 pp 3ndash26 2001

[32] A K Ghose V N Viswanadhan and J J Wendoloski ldquoAknowledge-based approach in designing combinatorial ormedicinal chemistry libraries for drug discovery 1 A qualitativeand quantitative characterization of known drug databasesrdquoJournal of Combinatorial Chemistry vol 1 pp 55ndash68 1999

[33] Z Bikadi and E Hazai ldquoApplication of the PM6 semi-em-pirical method to modeling proteins enhances docking ac-curacy of AutoDockrdquo Journal of Cheminformatics vol 1p 15 2009

[34] S S Azam A Saroosh N Zaman and S Raza ldquoRole ofN-acetylserotonin O-methyltransferase in bipolar disordersand its dynamicsrdquo Journal of Molecular Liquids vol 182pp 25ndash31 2013

[35] O Trott and A J Olson ldquoAutoDockVina improving thespeed and accuracy of docking with a new scoring functionefficient optimization and multi-threadingrdquo Journal ofComputational Chemistry vol 31 pp 455ndash461 2010

[36] G M Morris D S Goodsell R S Halliday et al ldquoAutomateddocking using a Lamarckian genetic algorithm and an em-pirical binding free energy functionrdquo Journal of Computa-tional Chemistry vol 19 no 14 pp 1639ndash1662 1998

[37] T A Halgren ldquoCharacterization of MMFF94 MMFF94s andother widely available force fields for conformational energiesand for intermolecular-interaction energies and geometriesrdquoJournal of Computational Chemistry vol 20 1999

[38] C Y Chung H Y Chung W T Sung et al ldquoMoleculardocking for protein folding structure and drug-likenessprediction WSEAS conferencerdquo International Journal ofBiology and Biomedicine vol 1 pp 57ndash63 2005

[39] G Li H Zhou Y Jiang et al ldquoDesign and synthesis of 4-arylpiperidinyl amide and N-arylpiperdin-3-yl-cyclopropanecarboxamide derivatives as novel melatonin receptor ligandsrdquoBioorganic amp Medicinal Chemistry Letters vol 21 no 4pp 1236ndash1242 2011

[40] F J Solis and R J B Wets ldquoMinimization by random searchtechniquesrdquoMathematics of Operations Research vol 6 no 1pp 19ndash30 1981

[41] I A Alswaidan K Sooknah L Rhyman et al ldquo2 4-Ditel-lurouracil and its 5-fluoro derivative )eoretical investiga-tions of structural energetics and ADME parametersrdquoComputational Biology and Chemistry vol 68 pp 56ndash632017

16 Evidence-Based Complementary and Alternative Medicine

[42] M F Fromm ldquoP-glycoprotein a defense mechanism limitingoral bioavailability and CNS accumulation of drugsrdquo Inter-national Journal of Clinical Pharmacology amp Eerapeuticsvol 38 no 2 pp 69ndash74 2000

[43] G Szakacs A Varadi C Ozvegy Laczka and B Sarkadi ldquo)erole of ABC transporters in drug absorption distributionmetabolism excretion and toxicity (ADME-Tox)rdquo Drug Dis-covery Today vol 13 no 9-10 pp 379ndash393 2008

[44] B Testa and S D Kraemer ldquo)e biochemistry of drugmetabolism an introduction part 2 Redox reactions and theirenzymesrdquo ChemInform vol 38 no 23 pp 257ndash405 2007

[45] S Meeran V Baskar S Syed Tajudeen and T K ShabeerldquoDesign ADME profiling and molecular docking simulationof new isoniazid schiff base analogs as MtKasB InhibitorsrdquoAsian Journal of Chemistry and Pharmaceutical Science vol 6pp 20ndash34 2018

[46] J B Baell and G A Holloway ldquoNew substructure filters forremoval of pan assay interference compounds (PAINS) fromscreening libraries and for their exclusion in bioassaysrdquoJournal of Medicinal Chemistry vol 53 no 7 pp 2719ndash27402010

[47] T J Ritchie P Ertl and R Lewis ldquo)e graphical represen-tation of ADME-related molecule properties for medicinalchemistsrdquo Drug Discovery Today vol 16 no 1-2 pp 65ndash722011

[48] Z M Dastjerdi F Namjoyan and M E Azemi ldquoAlphaamylase inhibition activity of some plants extract of Teucriumspeciesrdquo European Journal of Biological Sciences vol 7pp 26ndash31 2015

[49] I M E Lacroix and E C Y Li-Chan ldquoOverview of foodproducts and dietary constituents with antidiabetic propertiesand their putative mechanisms of action a natural approachto complement pharmacotherapy in the management of di-abetesrdquo Molecular Nutrition amp Food Research vol 58 no 1pp 61ndash78 2014

[50] H V Rupasinghe S Sekhon-Loodu T Mantso andM I Panayiotidis ldquoPhytochemicals in regulating fatty acidβ-oxidation Potential underlying mechanisms and their in-volvement in obesity and weight lossrdquo Pharmacology ampEerapeutics vol 165 pp 153ndash163 2016

[51] M Qasim Z Abideen M Y Adnan et al ldquoAntioxidantproperties phenolic composition bioactive compounds andnutritive value of medicinal halophytes commonly used asherbal teasrdquo South African Journal of Botany vol 110pp 240ndash250 2017

[52] B Romano E Pagano V Montanaro A L FortunatoNMilic and F Borrelli ldquoNovel insights into the pharmacologyof flavonoidsrdquo Phytotherapy Research vol 27 pp 1588ndash15962013

[53] A P Rauter A Martins C Borges et al ldquoAntihyperglycaemicand protective effects of flavonoids on streptozotocinndashinduceddiabetic ratsrdquo Phytotherapy Research vol 24 pp S133ndashS1382010

[54] M O Agbo P F Uzor U N Nneji C U OdurukweU B Ogbatue and E C Mbaoji ldquoAntioxidant total phenolicand flavonoid content of selected Nigerian medicinal plantsrdquoDhaka University Journal of Pharmaceutical Science vol 14pp 35ndash41 2015

[55] N Saeed M R Khan and M Shabbir ldquoAntioxidant activitytotal phenolic and total flavonoid contents of whole plantextracts Torilis leptophylla Lrdquo BMC Complementary andAlternative Medicine vol 12 no 1 p 221 2012

[56] M R Kumbhare V Guleha and T Sivakumar ldquoEstimationof total phenolic content cytotoxicity and inndashvitro

antioxidant activity of stem bark of Moringa oleiferardquo AsianPacific Journal of Tropical Disease vol 2 pp 144ndash150 2012

[57] A A Ala B B Olotu and C M D Ohia ldquoAssessment ofcytotoxicity of leaf extracts of andrographis paniculata andaspilia Africana onmurine cellsrdquoArchives of basic and appliedmedicine vol 6 pp 61ndash65 2018

[58] S K Doreddula S R Bonam D P Gaddam B S R DesuN Ramarao and V Pandy ldquoPhytochemical analysis antioxi-dant antistress and nootropic activities of aqueous andmethanolic seed extracts of ladies finger (Abelmoschus escu-lentus L) in micerdquo Ee Scientific World Journal vol 2014Article ID 519848 14 pages 2014

[59] L A Nistor Baldea L C Martineau A Benhaddou-Anda-loussi J T Arnason E Levy and P S Haddad ldquoInhibition ofintestinal glucose absorption by anti-diabetic medicinal plantsderived from the James Bay Cree traditional pharmacopeiardquoJournal of Ethnopharmacology vol 132 no 2 pp 473ndash4822010

[60] N Shehzadi K Hussain N I Bukhari et al ldquoHypoglycemichepatoprotective and molecular docking studies of 5-[(4-chlorophenoxy) methyl]-1 3 4- oxadiazole-2-thiolrdquo Ban-gladesh Journal of Pharmacology vol 13 no 2 pp 149ndash1562018

[61] D Seeliger B L de Groot and V De Pymol ldquoLigand dockingand binding site analysis with PyMOL and AutodockVinardquoJournal of Computer-Aided Molecular Design vol 24pp 417ndash422 2010

[62] W Benalla S Bellahcen and M Bnouham ldquoAntidiabeticmedicinal plants as a source of alpha glucosidase inhibitorsrdquoCurrent Diabetes Reviews vol 6 no 4 pp 247ndash254 2010

[63] R Andleeb M U Ijaz A Rafique et al ldquoBiological activitiesof methanolic extract of aegle marmelos against HN protein ofnewcastle disease virusrdquo Agronomy vol 11 no 9 p 17842021

Evidence-Based Complementary and Alternative Medicine 17

1395plusmn 133 to 2453plusmn 061 Agbo et al [54] reported flavo-noid values in M afzelii extract ie 367plusmn 000mg QEgwhile Saeed et al [55] reported the value of 596plusmn 15 formethanolic plant extract of T leptophylla

Previous research has shown that diabetic beta cellsproduce reactive oxygen species (ROS) which are coun-teracted by the overexpression of antioxidant enzymes suchas superoxide dismutase (SOD) catalase (CAT) and per-oxidase (POX) Antioxidants protect beta cells from oxi-dative damage by scavenging the free radicals produced thuspreventing diabetes from developing [27ndash29] In transgenicmice overexpression of SOD has been shown to prevent thedevelopment of diabetic complications Since oxidative stressis linked to the development of diabetic complications andinflammation this study aimed to assess Tabernaemontanadivaricatarsquos antioxidant activity

Biological properties such as the antioxidant propertyare considered as an estimation of the nutritional and

medicinal value of plants [56] )e antioxidant activity ofmethanolic extract of T divaricata flowers was estimated byDPPH assay DPPH is a neutral free radical that helps astable molecule to tolerate an electron or hydrogen radical)e ability of natural antioxidants to reduce the DPPH freeradical is assessed by a decrease in absorbance at 520 nm Incomparison with regular ascorbic acid the extract showedstrong scavenging activity )e lower the absorbance themore the scavenging operation there was As a result thebioactive compounds in this plant can serve as antioxidantsand aid in the treatment of a variety of diseases includingdiabetes Antioxidant properties of natural compounds aresaid to correlate with antidiabetic properties or vice versa Inthis study the given antioxidant activity of the T divaricataflower extract could be connected to their good amount ofTFC and TPC which function as metal chelators reductionagents hydrogen donors and singlet oxygen quenchers andfree radical scavenger [57]

LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(a)

LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(b)

LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(c)LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(d)

LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(e)

LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(f )LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(g)

LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(h)

LIPO

INSOLU

POLAR

SIZEFLEX

INSATU

(i)

Figure 2 Structures of bioavailability radar (a) 1610-dodecatriene 711-dimethyl-3-methylene (b) 2-phenylthiolane propanamide (c)phthalonitrile (d) cyclohexane propanoic acid (e) cyclopropane tetradecanoic acid (f ) N-methylallylamine (g) propanamide (h) 1H-tetrazol-5-amine and (i) cyclohexene 3-ethenyl

10 Evidence-Based Complementary and Alternative Medicine

Table 7 Nine selective compound properties of molecular formulaweight for docking

Name of the compound Molecular formula MW PubChem ID Structure

1610-Dodecatriene 711-dimethyl-3-methylene- (Z)- C15H24 204 5317319

H

Cyclohexane propanoic acid 3-oxo- methyl ester C10H16O3 184 538977 H3C

O

O

O

Cyclopropane tetradecanoic acid 2-octyl- methyl ester C26H50O2 394 552099 H

OO

H

4-(4-Methyl-2-biphenylyloxy) phthalonitrile C21H14N2O 310 628209

N

NC

C

O

2-Phenylthiolane C10H12S 16427 596288

OS

Propanamide C3H7NO 7309 6578NH2

H3C

O

Cyclohexene 3-ethenyl C8H12 10818 522623

H2C

N-Methylallylamine C4H10ClN 10758 18326499CH3H2C

NH

1H-Tetrazol-5-amine ltCH5N5O 10308 12211273 NH2NH

NN

N

Evidence-Based Complementary and Alternative Medicine 11

Toxicity is an important factor in the design of phar-maceutical drugs and an important starting point for he-molytic actions providing principal knowledge on theinteraction at the cellular level between biological entitiesand molecules Hemolytic activity of any compound is a signof common cytotoxicity towards normal healthy cells In thisresearch MEAE exhibited 10 cytotoxicity toward humanerythrocytes as shown in Table 3 Such findings demonstratethat if medicinal formulations from this plant are used at lowconcentrations parameters of the RBC membrane will notchange Reports on the toxic effects of A esculentus areinsufficient A previous study conducted with aqueous andmethanolic extracts of the A esculentus fruit confirmed thatthere were no deaths up to a dose of 2000mgkg (po) inSwiss mice (n 6) for 7 days and no signs of toxicity [58]which may be one of the significant issues for considering itas an important vegetable for human use Further research isessential on this medicinal edible plant in the context of drugdevelopment and discovery

Dietary phenols and flavonoids in accumulation totheir antioxidant effects have been noticed to exert anti-hyperglycemic effects by binding to the transporters of

glucose [49] and spirited digestive enzyme inhibition [59])e carbohydrate-digesting enzymes α-glucosidase andα-amylase digest dietary starch and produce glucoseresulting in surge of postprandial glucose So the inhibition ofα-glucosidase and α-amylase activities is one of the primaryapproaches to managing hyperglycemic T2D patients

T divaricata has antidiabetic activity according to al-pha-amylase inhibitory tests )e percentage inhibitoryactivity of plant methanolic extract against alpha-amylaseenzyme increased in a dose-dependent manner )e plantextract concentration of 50 gml showed a percentage in-hibition of 28 while 200 gml showed a percentage inhi-bition of 61 At a high concentration of 200 gml theextract inhibited the alpha-amylase enzyme by 50 As aresult of the current inhibitory studies it has been discoveredthat the T divaricata plant extract is successful in inhibitingthe alpha-amylase enzyme which helps to postpone thebreakdown of starch into glucose and thus maintain glucoselevels in diabetic patients Dastjerdi et al [48] observedα-amylase inhibition activity of some plant extracts of Teucrium species values ranged from 4159plusmn 064 to7707plusmn 049 at 156mgmL to 25mgmL )e α-amylase

Table 8 Docking interactions of different active compounds of T divaricate

Compound Goldscore

Gold bindingfitness RMSD Residue Hydrophobicity Pka Distance

2-phenylthiolane 0205 2914 7861

LEU777 38 476ARG779 minus45 12 384VAL784 42 492LEU846 38 509

4-(4-Methyl-2-biphenylyloxy) phthalonitrile minus653 3721 6918

LEU777 38 457ARG779 minus45 12 47ASN780 minus35 319THR782 minus07 234VAL784 42 508LEU846 38 220

Cyclohexanepropanoic acid 3-oxo- methyl ester minus093 2829 6543 ARG779 minus45 12 226VAL784 42 442

Cyclopropane tetradecanoic acid 2-octyl- methylester minus751 3928 6909

LEU777 38 532ARG779 minus45 12 461VAL784 42 502LEU815 38 508SER848 minus08 247TRP849 minus09 264CYS850 25 9 374

1610-Dodecatriene 711-dimethyl-3-methylene- minus403 3269 6703LEU777 38 513ARG779 minus45 12 499VAL784 42 388

N-Methylallylamine minus016 2000 6588

LEU777 38 408ARG779 minus45 12 370THR782 minus07 152VAL784 42 484

Propanamide minus059 1916 6542LEU777 38 220THR782 minus07 286VAL784 42 528

1H-Tetrazol-5-amine 000 1721 6678GLU750 minus35 43 259ARG779 minus45 12 185ASN780 minus35 274

Cyclohexene 3-ethenyl 014 2383 6450LEU777 38 497ARG779 minus45 12 389VAL784 42 435

12 Evidence-Based Complementary and Alternative Medicine

N-Methylallylamine

Interactions

Conventional Hydrogen Bond

Alkyl

Phthalonitrile

Interactions

Unfavorable Bump

Pi-Donor Hydrogen Bond

Alkyl

Pi-Alkyl

Cyclopropane tetradecanoic acid2-octyl- methyl ester

Interactions

Conventional Hydrogen Bond

Corbon Hydrogen Bond

Alkyl

1H-Tetrazol-5-amine

Interactions

Conventional Hydrogen Bond

Pi-Sigma

Pi-Alkyl

Cyclohexanepropanoic acid

Interactions

Conventional Hydrogen Bond

Alkyl

Cyclohexene 3-ethenyl

Interactions

Alkyl

(a)

Figure 3 Continued

Evidence-Based Complementary and Alternative Medicine 13

inhibitory activity of methanol plant extract is most likely bypolar compounds that should be investigated further byisolating pure active compounds

At 50ndash200 gml concentrations of T divaricata ex-tract the percentage inhibition increased in a dose-de-pendent manner For the highest and lowestconcentrations respectively the percentage inhibitionranged from 60 to 31 (Table 4) )us by inhibiting thealpha-glucosidase enzyme the extract of T divaricatawhich contains various natural bioactive compoundshelps to reduce the rate of carbohydrate digestionlowering blood glucose levels and maintaining diabeticconditions

Glucose uptake is one of the in vitro methods used toexplore the antihyperglycemic effect of different compounds[60] )e average values of glucose uptake by yeast cells inthis study were 1305plusmn 13 to 695plusmn 478 Shehzadi et al[60] reported the evaluation of antihyperglycemic activitythrough in vitro assays (02 to 263) at 2mgmL which wasbelow the current research values )e results indicated allused concentrations under examination are capable of in-creasing the utilization and uptake of glucose in yeast cells

)e in silico prediction of molecular physicochemicalparameters bioavailability and the pharmacokinetics havebecome more relevant for the investigation of productivepotential drug molecules from a drug discovery standpoint[47] )eoretical experiments play a critical role in presentingaccurate data in a timely and comfortable manner Many freeonline platforms have recently been established for fasterscreening reducing the time and expense of drug testing (noanimal testing) [46] SwissADME is a modern comprehensivemethod developed by the Swiss Institute of Bioinformatics(SIB) that allows drug candidates to have their absorptiondelivery metabolism and excretion (ADME) parametersestimated [45] At the outset of the drug development processADME properties which determine either the potentialdrugrsquos access to the target or its removal by the organism arethe required properties that must be evaluated for the drug tobe selected In silico experiments based on measured phys-icochemical requirements can be used to check these pa-rameters SwissADME also provides information ongastrointestinal absorption (GIA) and blood-brain barrier(BBB) permeability in humans From twenty-six selectedcompounds only eight compounds fulfilled the criteria of

1 6 10-Dodecatriene 7 11-dimethyl-3-methylene

Interactions

Alkyl

2-phenylthiolane Propanamide

Interactions

Alkyl

Pi-Alkyl

Propanamide

Interactions

Conventional Hydrogen Bond

Alkyl

(b)

Figure 3 In silico molecular docking results of interactions between 5kzw proteins with screened compounds as ligand

14 Evidence-Based Complementary and Alternative Medicine

drug-likeness parameters So all of these nine compoundswere further processed for molecular docking by GOLD

To predict the affinity and behavior of small moleculesand drug candidates computational molecular docking iscommonly used to predict the binding orientation to theirprotein targets [61] We used molecular docking to modelvarious bioactive compounds isolated from the Jasmineplant that is known to inhibit glucosidase Because of theirlow price and comparatively greater protection with a lowfrequency of severe gastrointestinal side effects plants orplant-based substances may be a suitable source of gluco-sidase inhibitors [62] Hydrogen bonds play a crucial role inthe structure and interaction of protein-protein or ligand-receptor complexes Hydrogen bonds are important in drugdesign to ensure that the drug is unique to the protein targetTo back up the findings of this research a molecular dockingstudy was performed (cyclopropane tetradecanoic acid 2-octyl- methyl ester 4-(4-methyl-2-biphenylyloxy) phtha-lonitrile) which showed excellent interaction with 5kzwprotein having Gold fitness (3928 3721) and GOLDdocking score of -751 and -653 including the formation ofhydrogen bond with amino acids residues (1610-dodeca-triene 711-dimethyl-3-methylene 2-phenylthiolane andcyclohexane propanoic acid 3-oxo- methyl ester) )esemolecules showed exceptionally good interaction withα-glucosidase protein and can be considered as potentialmolecules that may prove to be beneficial in antiviral activitythrough their direct action on new castle disease [63] )esecompounds showed moderate binding affinity of 32692914 and 2829 and GOLD docking scores of -403 0205and 093 respectively N-methylallylamine propanamidecyclohexene and 3-ethenyl have the least interaction in therange of 2000 1916 and 2383 and docking scores of -016-059 and 014 while 1H-tetrazol-5-amine compoundshowed the least affinity towards 5kzw binding site

5 Conclusion

Since diabetes mellitus is a global epidemic effective drugswith less or no toxicity must be developed and one such wayis the use of herbal medicines having no side effects )isstudy investigated the antidiabetic and antioxidant prop-erties of T divaricata extract and found promising inhibitorsof two carbohydrate-related enzymes T divaricata has richphenolic and flavonoid contents As a flavonoid it has greatantidiabetic potential and also causes active uptake of glu-cose )e methanolic extract of T divaricate has great po-tential for stimulation of α-amylase and α-glucosidase sothat it can be used to treat diabetes In silico docking studiesof phytoactive compounds from T divaricata have beenproven to have potential drug capabilities in terms of theirpharmacokinetic and drug-likeness )e molecular dockinganalysis described some compounds that inhibited thetargets related to diabetes mellitus and showed encouragingresults with prominent inhibitory activity )is study showsthat T divaricata extract which is rich in important bio-active compounds can be used for diabetes It is suggested tocarry out long-term research work to recognize and isolatethe active moieties responsible for antidiabetic property and

to understand the mechanisms involved in glucose-loweringproperties of the plant

Data Availability

Data are available from authors on reasonable demand

Conflicts of Interest

)e authors declare that there are no conflicts of interestregarding the publication of this study

Acknowledgments

)e facilities and support provided by the Department ofZoology Government College University Faisalabad arehighly acknowledged

References

[1] C D Deshmukh and A Jain ldquoDiabetes mellitus a reviewrdquoInternational Journal of Pure and Applied Biosciences vol 3pp 224ndash230 2015

[2] American Diabetes Association (ADA) ldquo5 Lifestyle man-agement Standards of medical care in diabetesmdash2019rdquo Di-abetes Care vol 42 no 1 pp S46ndashS60 2019

[3] A Meeinta C Rojwipaporn R Chanaporn et al ldquoDiabetesmellitus HbA1c and lung function do they are relatedrdquo Di-abetes amp its Complications vol 2 no 3 pp 1ndash6 2018

[4] U Yoon L L Kwok and A Magkidis ldquoEfficacy of lifestyleinterventions in reducing diabetes incidence in patients withimpaired glucose tolerance a systematic review of random-ized controlled trialsrdquo BMC Proceedings vol 6 pp P28ndashP142012

[5] S B Aynalem and A J Zeleke ldquoPrevalence of diabetesmellitus and its risk factors among individuals aged 15 yearsand above in Mizan-Aman town a cross sectional studyrdquoInternational Journal of Endocrinology vol 2018 Article ID9317987 7 pages 2018

[6] D R Whiting L Guariguata C Weil and J Shaw ldquoIDFdiabetes atlas global estimates of the prevalence of diabetesfor 2011 and 2030rdquo Diabetes Research and Clinical Practicevol 94 pp 311ndash321 2011

[7] P Agarwal and R Gupta ldquoAlpha-amylase inhibition can treatdiabetes mellitusrdquo Research Review Journal of Medical HealthScience vol 5 pp 1ndash8 2016

[8] H Kaneto N Katakami M Matsuhisa and T A MatsuokaldquoRole of reactive oxygen species in the progression of type 2diabetes and atherosclerosisrdquo Mediators of Inflammationvol 2010 Article ID 453892 11 pages 2010

[9] Z Sun and R Albert ldquoBoolean models of cellular signalingnetworksrdquo in Handbook of Systems BiologyElsevier Amster-dam Netherlands 2013

[10] M Nazıroglu ldquoNew molecular mechanisms on the activationof TRPM2 channels by oxidative stress and ADP-riboserdquoNeurochemical Research vol 32 pp 1990ndash2001 2007

[11] R Dringen ldquoOxidative and antioxidative potential of brainmicroglial cellsrdquo Antioxidants and Redox Signaling vol 7pp 1223ndash1233 2005

[12] T Zahidi A Lekchiri T Zahidi W Lekchiri and A BerrichialdquoExtraction and comparison of two new peroxidases fromleaves and roots of Brassica oleraceae var ramoserdquo Journal of

Evidence-Based Complementary and Alternative Medicine 15

Materials and Environmental Science vol 9 pp 1398ndash14042018

[13] D M Kasote S S Katyare M V Hegde and H BaeldquoSignificance of antioxidant potential of plants and its rele-vance to therapeutic applicationsrdquo International Journal ofBiological Sciences vol 11 pp 982ndash991 2015

[14] W Kooti M Farokhipour Z Asadzadeh D Ashtary-Larkyand M Asadi-Samani ldquo)e role of medicinal plants in thetreatment of diabetes a systematic reviewrdquo Electronic Phy-sician vol 8 no 1 pp 1832ndash1842 2016

[15] M S Aslam and M S Ahmad ldquoWorldwide importance ofmedicinal plants current and historical perspectivesrdquo RecentAdvances in Biology and Medicine vol 02 p 88 2016

[16] S Ponnusamy R Ravindran S Zinjarde S Bhargava andA R Kumar ldquoEvaluation of traditional Indian antidiabeticmedicinal plants for human pancreatic amylase inhibitoryeffect in vitrordquo Evidence-Based Complementary and Alter-native Medicine vol 2011 Article ID 515647 10 pages 2011

[17] P P Bijeshmon and S George ldquoAntimicrobial activity andpowder microscopy of the flowers of Tabernaemontanadivaricata Rrdquo BRrdquo Indo American Journal of PharmaceuticalResearch vol 4 pp 1601ndash1605 2014

[18] V L Singleton R Orthofer and R M Lamuela-RaventosldquoAnalysis of total phenols and other oxidation substrates andantioxidants by means of folin-ciocalteu reagentrdquoMethods inEnzymology vol 299 pp 152ndash178 1999

[19] J Bao Y Cai M Sun G Wang and H Corke ldquoAnthocy-anins flavonols and free radical scavenging activity of Chi-nese bayberry (Myrica rubra) extracts and their colorproperties and stabilityrdquo Journal of Agricultural and FoodChemistry vol 53 pp 2327ndash2332 2005

[20] M Mohebbi-Fani A Mirzaei S Nazifi and M R TabandehldquoOxidative status and antioxidant enzyme activities inerythrocytes from breeding and pregnant ewes grazing nat-ural pastures in dry seasonrdquo Revue de Medecine Veterinairevol 163 pp 454ndash460 2012

[21] G H Onsa N bin Saari J Selamat and J Bakar ldquoPurificationand characterization of membrane-bound peroxidases fromMetroxylon sagurdquo Food Chemistry vol 85 no 3 pp 365ndash3762004

[22] M Kumar A J Bijo R S Baghel C Reddy and B JhaldquoSelenium and spermine alleviate cadmium induced toxicityin the red seaweed Gracilaria dura by regulating antioxidantsand DNA methylationrdquo Plant Physiology and Biochemistryvol 51 pp 129ndash138 2012

[23] W A Powell C M Catranis and C A Maynard ldquoDesign ofself-processing antimicrobial peptides for plant protectionrdquoLetters in Applied Microbiology vol 31 pp 163ndash168 2000

[24] L J Shai P Masoko M P Mokgotho et al ldquoYeast alphaglucosidase inhibitory and antioxidant activities of six me-dicinal plants collected in Phalaborwa South Africardquo SouthAfrican Journal of Botany vol 76 pp 465ndash470 2010

[25] A O Ademiluyi and G Oboh ldquoSoybean phenolic-rich extractsinhibit key-enzymes linked to type 2 diabetes (α-amylase andα-glucosidase) and hypertension (angiotensin I convertingenzyme) in vitrordquo Experimental amp Toxicologic Pathologyvol 65 pp 305ndash309 2013

[26] V P Cirillo ldquoMechanism of glucose transport across the yeastcell membranerdquo Journal of Bacteriology vol 84 pp 485ndash4911962

[27] C Kalaimagal ldquoIdentification of bioactive compounds inflower of Tabernaemontana divaricata (l) using gas chro-matographyndashmass spectrometry analysisrdquo Asian Journal of

Pharmaceutical and Clinical Research vol 12 pp 129ndash1322019

[28] H H Rassem A Hamid Nour and R Mohamed YunusldquoAnalysis of bioactive compounds for Jasmine flower via Gaschromatography-mass spectrometry (GC-MS)rdquo MalaysianJournal of Fundamental and Applied Sciences vol 14 no 2pp 198ndash201 2018

[29] M S Ali Khan AMMat Jais and A Afreen ldquoAnalogous andantioxidant activity mediated gastroprotective action ofTabernaemontana divaricata (L) R Br flower methanolicextract against chemically induced gastric ulcers in ratsrdquoBioMed Research International vol 2013 Article ID 18547618 pages 2013

[30] D F Veber S R Johnson H Y Cheng B R SmithK W Ward and K D Kopple ldquoMolecular properties thatinfluence the oral bioavailability of drug candidatesrdquo Journalof Medicinal Chemistry vol 45 no 12 pp 2615ndash2623 2002

[31] C A Lipinski A Lombardo B W Dominy F Dominy andP J Feeney ldquoExperimental and computational approaches toestimate solubility and permeability in drug discovery anddevelopment settingsrdquo Advanced Drug Delivery Reviewsvol 46 pp 3ndash26 2001

[32] A K Ghose V N Viswanadhan and J J Wendoloski ldquoAknowledge-based approach in designing combinatorial ormedicinal chemistry libraries for drug discovery 1 A qualitativeand quantitative characterization of known drug databasesrdquoJournal of Combinatorial Chemistry vol 1 pp 55ndash68 1999

[33] Z Bikadi and E Hazai ldquoApplication of the PM6 semi-em-pirical method to modeling proteins enhances docking ac-curacy of AutoDockrdquo Journal of Cheminformatics vol 1p 15 2009

[34] S S Azam A Saroosh N Zaman and S Raza ldquoRole ofN-acetylserotonin O-methyltransferase in bipolar disordersand its dynamicsrdquo Journal of Molecular Liquids vol 182pp 25ndash31 2013

[35] O Trott and A J Olson ldquoAutoDockVina improving thespeed and accuracy of docking with a new scoring functionefficient optimization and multi-threadingrdquo Journal ofComputational Chemistry vol 31 pp 455ndash461 2010

[36] G M Morris D S Goodsell R S Halliday et al ldquoAutomateddocking using a Lamarckian genetic algorithm and an em-pirical binding free energy functionrdquo Journal of Computa-tional Chemistry vol 19 no 14 pp 1639ndash1662 1998

[37] T A Halgren ldquoCharacterization of MMFF94 MMFF94s andother widely available force fields for conformational energiesand for intermolecular-interaction energies and geometriesrdquoJournal of Computational Chemistry vol 20 1999

[38] C Y Chung H Y Chung W T Sung et al ldquoMoleculardocking for protein folding structure and drug-likenessprediction WSEAS conferencerdquo International Journal ofBiology and Biomedicine vol 1 pp 57ndash63 2005

[39] G Li H Zhou Y Jiang et al ldquoDesign and synthesis of 4-arylpiperidinyl amide and N-arylpiperdin-3-yl-cyclopropanecarboxamide derivatives as novel melatonin receptor ligandsrdquoBioorganic amp Medicinal Chemistry Letters vol 21 no 4pp 1236ndash1242 2011

[40] F J Solis and R J B Wets ldquoMinimization by random searchtechniquesrdquoMathematics of Operations Research vol 6 no 1pp 19ndash30 1981

[41] I A Alswaidan K Sooknah L Rhyman et al ldquo2 4-Ditel-lurouracil and its 5-fluoro derivative )eoretical investiga-tions of structural energetics and ADME parametersrdquoComputational Biology and Chemistry vol 68 pp 56ndash632017

16 Evidence-Based Complementary and Alternative Medicine

[42] M F Fromm ldquoP-glycoprotein a defense mechanism limitingoral bioavailability and CNS accumulation of drugsrdquo Inter-national Journal of Clinical Pharmacology amp Eerapeuticsvol 38 no 2 pp 69ndash74 2000

[43] G Szakacs A Varadi C Ozvegy Laczka and B Sarkadi ldquo)erole of ABC transporters in drug absorption distributionmetabolism excretion and toxicity (ADME-Tox)rdquo Drug Dis-covery Today vol 13 no 9-10 pp 379ndash393 2008

[44] B Testa and S D Kraemer ldquo)e biochemistry of drugmetabolism an introduction part 2 Redox reactions and theirenzymesrdquo ChemInform vol 38 no 23 pp 257ndash405 2007

[45] S Meeran V Baskar S Syed Tajudeen and T K ShabeerldquoDesign ADME profiling and molecular docking simulationof new isoniazid schiff base analogs as MtKasB InhibitorsrdquoAsian Journal of Chemistry and Pharmaceutical Science vol 6pp 20ndash34 2018

[46] J B Baell and G A Holloway ldquoNew substructure filters forremoval of pan assay interference compounds (PAINS) fromscreening libraries and for their exclusion in bioassaysrdquoJournal of Medicinal Chemistry vol 53 no 7 pp 2719ndash27402010

[47] T J Ritchie P Ertl and R Lewis ldquo)e graphical represen-tation of ADME-related molecule properties for medicinalchemistsrdquo Drug Discovery Today vol 16 no 1-2 pp 65ndash722011

[48] Z M Dastjerdi F Namjoyan and M E Azemi ldquoAlphaamylase inhibition activity of some plants extract of Teucriumspeciesrdquo European Journal of Biological Sciences vol 7pp 26ndash31 2015

[49] I M E Lacroix and E C Y Li-Chan ldquoOverview of foodproducts and dietary constituents with antidiabetic propertiesand their putative mechanisms of action a natural approachto complement pharmacotherapy in the management of di-abetesrdquo Molecular Nutrition amp Food Research vol 58 no 1pp 61ndash78 2014

[50] H V Rupasinghe S Sekhon-Loodu T Mantso andM I Panayiotidis ldquoPhytochemicals in regulating fatty acidβ-oxidation Potential underlying mechanisms and their in-volvement in obesity and weight lossrdquo Pharmacology ampEerapeutics vol 165 pp 153ndash163 2016

[51] M Qasim Z Abideen M Y Adnan et al ldquoAntioxidantproperties phenolic composition bioactive compounds andnutritive value of medicinal halophytes commonly used asherbal teasrdquo South African Journal of Botany vol 110pp 240ndash250 2017

[52] B Romano E Pagano V Montanaro A L FortunatoNMilic and F Borrelli ldquoNovel insights into the pharmacologyof flavonoidsrdquo Phytotherapy Research vol 27 pp 1588ndash15962013

[53] A P Rauter A Martins C Borges et al ldquoAntihyperglycaemicand protective effects of flavonoids on streptozotocinndashinduceddiabetic ratsrdquo Phytotherapy Research vol 24 pp S133ndashS1382010

[54] M O Agbo P F Uzor U N Nneji C U OdurukweU B Ogbatue and E C Mbaoji ldquoAntioxidant total phenolicand flavonoid content of selected Nigerian medicinal plantsrdquoDhaka University Journal of Pharmaceutical Science vol 14pp 35ndash41 2015

[55] N Saeed M R Khan and M Shabbir ldquoAntioxidant activitytotal phenolic and total flavonoid contents of whole plantextracts Torilis leptophylla Lrdquo BMC Complementary andAlternative Medicine vol 12 no 1 p 221 2012

[56] M R Kumbhare V Guleha and T Sivakumar ldquoEstimationof total phenolic content cytotoxicity and inndashvitro

antioxidant activity of stem bark of Moringa oleiferardquo AsianPacific Journal of Tropical Disease vol 2 pp 144ndash150 2012

[57] A A Ala B B Olotu and C M D Ohia ldquoAssessment ofcytotoxicity of leaf extracts of andrographis paniculata andaspilia Africana onmurine cellsrdquoArchives of basic and appliedmedicine vol 6 pp 61ndash65 2018

[58] S K Doreddula S R Bonam D P Gaddam B S R DesuN Ramarao and V Pandy ldquoPhytochemical analysis antioxi-dant antistress and nootropic activities of aqueous andmethanolic seed extracts of ladies finger (Abelmoschus escu-lentus L) in micerdquo Ee Scientific World Journal vol 2014Article ID 519848 14 pages 2014

[59] L A Nistor Baldea L C Martineau A Benhaddou-Anda-loussi J T Arnason E Levy and P S Haddad ldquoInhibition ofintestinal glucose absorption by anti-diabetic medicinal plantsderived from the James Bay Cree traditional pharmacopeiardquoJournal of Ethnopharmacology vol 132 no 2 pp 473ndash4822010

[60] N Shehzadi K Hussain N I Bukhari et al ldquoHypoglycemichepatoprotective and molecular docking studies of 5-[(4-chlorophenoxy) methyl]-1 3 4- oxadiazole-2-thiolrdquo Ban-gladesh Journal of Pharmacology vol 13 no 2 pp 149ndash1562018

[61] D Seeliger B L de Groot and V De Pymol ldquoLigand dockingand binding site analysis with PyMOL and AutodockVinardquoJournal of Computer-Aided Molecular Design vol 24pp 417ndash422 2010

[62] W Benalla S Bellahcen and M Bnouham ldquoAntidiabeticmedicinal plants as a source of alpha glucosidase inhibitorsrdquoCurrent Diabetes Reviews vol 6 no 4 pp 247ndash254 2010

[63] R Andleeb M U Ijaz A Rafique et al ldquoBiological activitiesof methanolic extract of aegle marmelos against HN protein ofnewcastle disease virusrdquo Agronomy vol 11 no 9 p 17842021

Evidence-Based Complementary and Alternative Medicine 17

Table 7 Nine selective compound properties of molecular formulaweight for docking

Name of the compound Molecular formula MW PubChem ID Structure

1610-Dodecatriene 711-dimethyl-3-methylene- (Z)- C15H24 204 5317319

H

Cyclohexane propanoic acid 3-oxo- methyl ester C10H16O3 184 538977 H3C

O

O

O

Cyclopropane tetradecanoic acid 2-octyl- methyl ester C26H50O2 394 552099 H

OO

H

4-(4-Methyl-2-biphenylyloxy) phthalonitrile C21H14N2O 310 628209

N

NC

C

O

2-Phenylthiolane C10H12S 16427 596288

OS

Propanamide C3H7NO 7309 6578NH2

H3C

O

Cyclohexene 3-ethenyl C8H12 10818 522623

H2C

N-Methylallylamine C4H10ClN 10758 18326499CH3H2C

NH

1H-Tetrazol-5-amine ltCH5N5O 10308 12211273 NH2NH

NN

N

Evidence-Based Complementary and Alternative Medicine 11

Toxicity is an important factor in the design of phar-maceutical drugs and an important starting point for he-molytic actions providing principal knowledge on theinteraction at the cellular level between biological entitiesand molecules Hemolytic activity of any compound is a signof common cytotoxicity towards normal healthy cells In thisresearch MEAE exhibited 10 cytotoxicity toward humanerythrocytes as shown in Table 3 Such findings demonstratethat if medicinal formulations from this plant are used at lowconcentrations parameters of the RBC membrane will notchange Reports on the toxic effects of A esculentus areinsufficient A previous study conducted with aqueous andmethanolic extracts of the A esculentus fruit confirmed thatthere were no deaths up to a dose of 2000mgkg (po) inSwiss mice (n 6) for 7 days and no signs of toxicity [58]which may be one of the significant issues for considering itas an important vegetable for human use Further research isessential on this medicinal edible plant in the context of drugdevelopment and discovery

Dietary phenols and flavonoids in accumulation totheir antioxidant effects have been noticed to exert anti-hyperglycemic effects by binding to the transporters of

glucose [49] and spirited digestive enzyme inhibition [59])e carbohydrate-digesting enzymes α-glucosidase andα-amylase digest dietary starch and produce glucoseresulting in surge of postprandial glucose So the inhibition ofα-glucosidase and α-amylase activities is one of the primaryapproaches to managing hyperglycemic T2D patients

T divaricata has antidiabetic activity according to al-pha-amylase inhibitory tests )e percentage inhibitoryactivity of plant methanolic extract against alpha-amylaseenzyme increased in a dose-dependent manner )e plantextract concentration of 50 gml showed a percentage in-hibition of 28 while 200 gml showed a percentage inhi-bition of 61 At a high concentration of 200 gml theextract inhibited the alpha-amylase enzyme by 50 As aresult of the current inhibitory studies it has been discoveredthat the T divaricata plant extract is successful in inhibitingthe alpha-amylase enzyme which helps to postpone thebreakdown of starch into glucose and thus maintain glucoselevels in diabetic patients Dastjerdi et al [48] observedα-amylase inhibition activity of some plant extracts of Teucrium species values ranged from 4159plusmn 064 to7707plusmn 049 at 156mgmL to 25mgmL )e α-amylase

Table 8 Docking interactions of different active compounds of T divaricate

Compound Goldscore

Gold bindingfitness RMSD Residue Hydrophobicity Pka Distance

2-phenylthiolane 0205 2914 7861

LEU777 38 476ARG779 minus45 12 384VAL784 42 492LEU846 38 509

4-(4-Methyl-2-biphenylyloxy) phthalonitrile minus653 3721 6918

LEU777 38 457ARG779 minus45 12 47ASN780 minus35 319THR782 minus07 234VAL784 42 508LEU846 38 220

Cyclohexanepropanoic acid 3-oxo- methyl ester minus093 2829 6543 ARG779 minus45 12 226VAL784 42 442

Cyclopropane tetradecanoic acid 2-octyl- methylester minus751 3928 6909

LEU777 38 532ARG779 minus45 12 461VAL784 42 502LEU815 38 508SER848 minus08 247TRP849 minus09 264CYS850 25 9 374

1610-Dodecatriene 711-dimethyl-3-methylene- minus403 3269 6703LEU777 38 513ARG779 minus45 12 499VAL784 42 388

N-Methylallylamine minus016 2000 6588

LEU777 38 408ARG779 minus45 12 370THR782 minus07 152VAL784 42 484

Propanamide minus059 1916 6542LEU777 38 220THR782 minus07 286VAL784 42 528

1H-Tetrazol-5-amine 000 1721 6678GLU750 minus35 43 259ARG779 minus45 12 185ASN780 minus35 274

Cyclohexene 3-ethenyl 014 2383 6450LEU777 38 497ARG779 minus45 12 389VAL784 42 435

12 Evidence-Based Complementary and Alternative Medicine

N-Methylallylamine

Interactions

Conventional Hydrogen Bond

Alkyl

Phthalonitrile

Interactions

Unfavorable Bump

Pi-Donor Hydrogen Bond

Alkyl

Pi-Alkyl

Cyclopropane tetradecanoic acid2-octyl- methyl ester

Interactions

Conventional Hydrogen Bond

Corbon Hydrogen Bond

Alkyl

1H-Tetrazol-5-amine

Interactions

Conventional Hydrogen Bond

Pi-Sigma

Pi-Alkyl

Cyclohexanepropanoic acid

Interactions

Conventional Hydrogen Bond

Alkyl

Cyclohexene 3-ethenyl

Interactions

Alkyl

(a)

Figure 3 Continued

Evidence-Based Complementary and Alternative Medicine 13

inhibitory activity of methanol plant extract is most likely bypolar compounds that should be investigated further byisolating pure active compounds

At 50ndash200 gml concentrations of T divaricata ex-tract the percentage inhibition increased in a dose-de-pendent manner For the highest and lowestconcentrations respectively the percentage inhibitionranged from 60 to 31 (Table 4) )us by inhibiting thealpha-glucosidase enzyme the extract of T divaricatawhich contains various natural bioactive compoundshelps to reduce the rate of carbohydrate digestionlowering blood glucose levels and maintaining diabeticconditions

Glucose uptake is one of the in vitro methods used toexplore the antihyperglycemic effect of different compounds[60] )e average values of glucose uptake by yeast cells inthis study were 1305plusmn 13 to 695plusmn 478 Shehzadi et al[60] reported the evaluation of antihyperglycemic activitythrough in vitro assays (02 to 263) at 2mgmL which wasbelow the current research values )e results indicated allused concentrations under examination are capable of in-creasing the utilization and uptake of glucose in yeast cells

)e in silico prediction of molecular physicochemicalparameters bioavailability and the pharmacokinetics havebecome more relevant for the investigation of productivepotential drug molecules from a drug discovery standpoint[47] )eoretical experiments play a critical role in presentingaccurate data in a timely and comfortable manner Many freeonline platforms have recently been established for fasterscreening reducing the time and expense of drug testing (noanimal testing) [46] SwissADME is a modern comprehensivemethod developed by the Swiss Institute of Bioinformatics(SIB) that allows drug candidates to have their absorptiondelivery metabolism and excretion (ADME) parametersestimated [45] At the outset of the drug development processADME properties which determine either the potentialdrugrsquos access to the target or its removal by the organism arethe required properties that must be evaluated for the drug tobe selected In silico experiments based on measured phys-icochemical requirements can be used to check these pa-rameters SwissADME also provides information ongastrointestinal absorption (GIA) and blood-brain barrier(BBB) permeability in humans From twenty-six selectedcompounds only eight compounds fulfilled the criteria of

1 6 10-Dodecatriene 7 11-dimethyl-3-methylene

Interactions

Alkyl

2-phenylthiolane Propanamide

Interactions

Alkyl

Pi-Alkyl

Propanamide

Interactions

Conventional Hydrogen Bond

Alkyl

(b)

Figure 3 In silico molecular docking results of interactions between 5kzw proteins with screened compounds as ligand

14 Evidence-Based Complementary and Alternative Medicine

drug-likeness parameters So all of these nine compoundswere further processed for molecular docking by GOLD

To predict the affinity and behavior of small moleculesand drug candidates computational molecular docking iscommonly used to predict the binding orientation to theirprotein targets [61] We used molecular docking to modelvarious bioactive compounds isolated from the Jasmineplant that is known to inhibit glucosidase Because of theirlow price and comparatively greater protection with a lowfrequency of severe gastrointestinal side effects plants orplant-based substances may be a suitable source of gluco-sidase inhibitors [62] Hydrogen bonds play a crucial role inthe structure and interaction of protein-protein or ligand-receptor complexes Hydrogen bonds are important in drugdesign to ensure that the drug is unique to the protein targetTo back up the findings of this research a molecular dockingstudy was performed (cyclopropane tetradecanoic acid 2-octyl- methyl ester 4-(4-methyl-2-biphenylyloxy) phtha-lonitrile) which showed excellent interaction with 5kzwprotein having Gold fitness (3928 3721) and GOLDdocking score of -751 and -653 including the formation ofhydrogen bond with amino acids residues (1610-dodeca-triene 711-dimethyl-3-methylene 2-phenylthiolane andcyclohexane propanoic acid 3-oxo- methyl ester) )esemolecules showed exceptionally good interaction withα-glucosidase protein and can be considered as potentialmolecules that may prove to be beneficial in antiviral activitythrough their direct action on new castle disease [63] )esecompounds showed moderate binding affinity of 32692914 and 2829 and GOLD docking scores of -403 0205and 093 respectively N-methylallylamine propanamidecyclohexene and 3-ethenyl have the least interaction in therange of 2000 1916 and 2383 and docking scores of -016-059 and 014 while 1H-tetrazol-5-amine compoundshowed the least affinity towards 5kzw binding site

5 Conclusion

Since diabetes mellitus is a global epidemic effective drugswith less or no toxicity must be developed and one such wayis the use of herbal medicines having no side effects )isstudy investigated the antidiabetic and antioxidant prop-erties of T divaricata extract and found promising inhibitorsof two carbohydrate-related enzymes T divaricata has richphenolic and flavonoid contents As a flavonoid it has greatantidiabetic potential and also causes active uptake of glu-cose )e methanolic extract of T divaricate has great po-tential for stimulation of α-amylase and α-glucosidase sothat it can be used to treat diabetes In silico docking studiesof phytoactive compounds from T divaricata have beenproven to have potential drug capabilities in terms of theirpharmacokinetic and drug-likeness )e molecular dockinganalysis described some compounds that inhibited thetargets related to diabetes mellitus and showed encouragingresults with prominent inhibitory activity )is study showsthat T divaricata extract which is rich in important bio-active compounds can be used for diabetes It is suggested tocarry out long-term research work to recognize and isolatethe active moieties responsible for antidiabetic property and

to understand the mechanisms involved in glucose-loweringproperties of the plant

Data Availability

Data are available from authors on reasonable demand

Conflicts of Interest

)e authors declare that there are no conflicts of interestregarding the publication of this study

Acknowledgments

)e facilities and support provided by the Department ofZoology Government College University Faisalabad arehighly acknowledged

References

[1] C D Deshmukh and A Jain ldquoDiabetes mellitus a reviewrdquoInternational Journal of Pure and Applied Biosciences vol 3pp 224ndash230 2015

[2] American Diabetes Association (ADA) ldquo5 Lifestyle man-agement Standards of medical care in diabetesmdash2019rdquo Di-abetes Care vol 42 no 1 pp S46ndashS60 2019

[3] A Meeinta C Rojwipaporn R Chanaporn et al ldquoDiabetesmellitus HbA1c and lung function do they are relatedrdquo Di-abetes amp its Complications vol 2 no 3 pp 1ndash6 2018

[4] U Yoon L L Kwok and A Magkidis ldquoEfficacy of lifestyleinterventions in reducing diabetes incidence in patients withimpaired glucose tolerance a systematic review of random-ized controlled trialsrdquo BMC Proceedings vol 6 pp P28ndashP142012

[5] S B Aynalem and A J Zeleke ldquoPrevalence of diabetesmellitus and its risk factors among individuals aged 15 yearsand above in Mizan-Aman town a cross sectional studyrdquoInternational Journal of Endocrinology vol 2018 Article ID9317987 7 pages 2018

[6] D R Whiting L Guariguata C Weil and J Shaw ldquoIDFdiabetes atlas global estimates of the prevalence of diabetesfor 2011 and 2030rdquo Diabetes Research and Clinical Practicevol 94 pp 311ndash321 2011

[7] P Agarwal and R Gupta ldquoAlpha-amylase inhibition can treatdiabetes mellitusrdquo Research Review Journal of Medical HealthScience vol 5 pp 1ndash8 2016

[8] H Kaneto N Katakami M Matsuhisa and T A MatsuokaldquoRole of reactive oxygen species in the progression of type 2diabetes and atherosclerosisrdquo Mediators of Inflammationvol 2010 Article ID 453892 11 pages 2010

[9] Z Sun and R Albert ldquoBoolean models of cellular signalingnetworksrdquo in Handbook of Systems BiologyElsevier Amster-dam Netherlands 2013

[10] M Nazıroglu ldquoNew molecular mechanisms on the activationof TRPM2 channels by oxidative stress and ADP-riboserdquoNeurochemical Research vol 32 pp 1990ndash2001 2007

[11] R Dringen ldquoOxidative and antioxidative potential of brainmicroglial cellsrdquo Antioxidants and Redox Signaling vol 7pp 1223ndash1233 2005

[12] T Zahidi A Lekchiri T Zahidi W Lekchiri and A BerrichialdquoExtraction and comparison of two new peroxidases fromleaves and roots of Brassica oleraceae var ramoserdquo Journal of

Evidence-Based Complementary and Alternative Medicine 15

Materials and Environmental Science vol 9 pp 1398ndash14042018

[13] D M Kasote S S Katyare M V Hegde and H BaeldquoSignificance of antioxidant potential of plants and its rele-vance to therapeutic applicationsrdquo International Journal ofBiological Sciences vol 11 pp 982ndash991 2015

[14] W Kooti M Farokhipour Z Asadzadeh D Ashtary-Larkyand M Asadi-Samani ldquo)e role of medicinal plants in thetreatment of diabetes a systematic reviewrdquo Electronic Phy-sician vol 8 no 1 pp 1832ndash1842 2016

[15] M S Aslam and M S Ahmad ldquoWorldwide importance ofmedicinal plants current and historical perspectivesrdquo RecentAdvances in Biology and Medicine vol 02 p 88 2016

[16] S Ponnusamy R Ravindran S Zinjarde S Bhargava andA R Kumar ldquoEvaluation of traditional Indian antidiabeticmedicinal plants for human pancreatic amylase inhibitoryeffect in vitrordquo Evidence-Based Complementary and Alter-native Medicine vol 2011 Article ID 515647 10 pages 2011

[17] P P Bijeshmon and S George ldquoAntimicrobial activity andpowder microscopy of the flowers of Tabernaemontanadivaricata Rrdquo BRrdquo Indo American Journal of PharmaceuticalResearch vol 4 pp 1601ndash1605 2014

[18] V L Singleton R Orthofer and R M Lamuela-RaventosldquoAnalysis of total phenols and other oxidation substrates andantioxidants by means of folin-ciocalteu reagentrdquoMethods inEnzymology vol 299 pp 152ndash178 1999

[19] J Bao Y Cai M Sun G Wang and H Corke ldquoAnthocy-anins flavonols and free radical scavenging activity of Chi-nese bayberry (Myrica rubra) extracts and their colorproperties and stabilityrdquo Journal of Agricultural and FoodChemistry vol 53 pp 2327ndash2332 2005

[20] M Mohebbi-Fani A Mirzaei S Nazifi and M R TabandehldquoOxidative status and antioxidant enzyme activities inerythrocytes from breeding and pregnant ewes grazing nat-ural pastures in dry seasonrdquo Revue de Medecine Veterinairevol 163 pp 454ndash460 2012

[21] G H Onsa N bin Saari J Selamat and J Bakar ldquoPurificationand characterization of membrane-bound peroxidases fromMetroxylon sagurdquo Food Chemistry vol 85 no 3 pp 365ndash3762004

[22] M Kumar A J Bijo R S Baghel C Reddy and B JhaldquoSelenium and spermine alleviate cadmium induced toxicityin the red seaweed Gracilaria dura by regulating antioxidantsand DNA methylationrdquo Plant Physiology and Biochemistryvol 51 pp 129ndash138 2012

[23] W A Powell C M Catranis and C A Maynard ldquoDesign ofself-processing antimicrobial peptides for plant protectionrdquoLetters in Applied Microbiology vol 31 pp 163ndash168 2000

[24] L J Shai P Masoko M P Mokgotho et al ldquoYeast alphaglucosidase inhibitory and antioxidant activities of six me-dicinal plants collected in Phalaborwa South Africardquo SouthAfrican Journal of Botany vol 76 pp 465ndash470 2010

[25] A O Ademiluyi and G Oboh ldquoSoybean phenolic-rich extractsinhibit key-enzymes linked to type 2 diabetes (α-amylase andα-glucosidase) and hypertension (angiotensin I convertingenzyme) in vitrordquo Experimental amp Toxicologic Pathologyvol 65 pp 305ndash309 2013

[26] V P Cirillo ldquoMechanism of glucose transport across the yeastcell membranerdquo Journal of Bacteriology vol 84 pp 485ndash4911962

[27] C Kalaimagal ldquoIdentification of bioactive compounds inflower of Tabernaemontana divaricata (l) using gas chro-matographyndashmass spectrometry analysisrdquo Asian Journal of

Pharmaceutical and Clinical Research vol 12 pp 129ndash1322019

[28] H H Rassem A Hamid Nour and R Mohamed YunusldquoAnalysis of bioactive compounds for Jasmine flower via Gaschromatography-mass spectrometry (GC-MS)rdquo MalaysianJournal of Fundamental and Applied Sciences vol 14 no 2pp 198ndash201 2018

[29] M S Ali Khan AMMat Jais and A Afreen ldquoAnalogous andantioxidant activity mediated gastroprotective action ofTabernaemontana divaricata (L) R Br flower methanolicextract against chemically induced gastric ulcers in ratsrdquoBioMed Research International vol 2013 Article ID 18547618 pages 2013

[30] D F Veber S R Johnson H Y Cheng B R SmithK W Ward and K D Kopple ldquoMolecular properties thatinfluence the oral bioavailability of drug candidatesrdquo Journalof Medicinal Chemistry vol 45 no 12 pp 2615ndash2623 2002

[31] C A Lipinski A Lombardo B W Dominy F Dominy andP J Feeney ldquoExperimental and computational approaches toestimate solubility and permeability in drug discovery anddevelopment settingsrdquo Advanced Drug Delivery Reviewsvol 46 pp 3ndash26 2001

[32] A K Ghose V N Viswanadhan and J J Wendoloski ldquoAknowledge-based approach in designing combinatorial ormedicinal chemistry libraries for drug discovery 1 A qualitativeand quantitative characterization of known drug databasesrdquoJournal of Combinatorial Chemistry vol 1 pp 55ndash68 1999

[33] Z Bikadi and E Hazai ldquoApplication of the PM6 semi-em-pirical method to modeling proteins enhances docking ac-curacy of AutoDockrdquo Journal of Cheminformatics vol 1p 15 2009

[34] S S Azam A Saroosh N Zaman and S Raza ldquoRole ofN-acetylserotonin O-methyltransferase in bipolar disordersand its dynamicsrdquo Journal of Molecular Liquids vol 182pp 25ndash31 2013

[35] O Trott and A J Olson ldquoAutoDockVina improving thespeed and accuracy of docking with a new scoring functionefficient optimization and multi-threadingrdquo Journal ofComputational Chemistry vol 31 pp 455ndash461 2010

[36] G M Morris D S Goodsell R S Halliday et al ldquoAutomateddocking using a Lamarckian genetic algorithm and an em-pirical binding free energy functionrdquo Journal of Computa-tional Chemistry vol 19 no 14 pp 1639ndash1662 1998

[37] T A Halgren ldquoCharacterization of MMFF94 MMFF94s andother widely available force fields for conformational energiesand for intermolecular-interaction energies and geometriesrdquoJournal of Computational Chemistry vol 20 1999

[38] C Y Chung H Y Chung W T Sung et al ldquoMoleculardocking for protein folding structure and drug-likenessprediction WSEAS conferencerdquo International Journal ofBiology and Biomedicine vol 1 pp 57ndash63 2005

[39] G Li H Zhou Y Jiang et al ldquoDesign and synthesis of 4-arylpiperidinyl amide and N-arylpiperdin-3-yl-cyclopropanecarboxamide derivatives as novel melatonin receptor ligandsrdquoBioorganic amp Medicinal Chemistry Letters vol 21 no 4pp 1236ndash1242 2011

[40] F J Solis and R J B Wets ldquoMinimization by random searchtechniquesrdquoMathematics of Operations Research vol 6 no 1pp 19ndash30 1981

[41] I A Alswaidan K Sooknah L Rhyman et al ldquo2 4-Ditel-lurouracil and its 5-fluoro derivative )eoretical investiga-tions of structural energetics and ADME parametersrdquoComputational Biology and Chemistry vol 68 pp 56ndash632017

16 Evidence-Based Complementary and Alternative Medicine

[42] M F Fromm ldquoP-glycoprotein a defense mechanism limitingoral bioavailability and CNS accumulation of drugsrdquo Inter-national Journal of Clinical Pharmacology amp Eerapeuticsvol 38 no 2 pp 69ndash74 2000

[43] G Szakacs A Varadi C Ozvegy Laczka and B Sarkadi ldquo)erole of ABC transporters in drug absorption distributionmetabolism excretion and toxicity (ADME-Tox)rdquo Drug Dis-covery Today vol 13 no 9-10 pp 379ndash393 2008

[44] B Testa and S D Kraemer ldquo)e biochemistry of drugmetabolism an introduction part 2 Redox reactions and theirenzymesrdquo ChemInform vol 38 no 23 pp 257ndash405 2007

[45] S Meeran V Baskar S Syed Tajudeen and T K ShabeerldquoDesign ADME profiling and molecular docking simulationof new isoniazid schiff base analogs as MtKasB InhibitorsrdquoAsian Journal of Chemistry and Pharmaceutical Science vol 6pp 20ndash34 2018

[46] J B Baell and G A Holloway ldquoNew substructure filters forremoval of pan assay interference compounds (PAINS) fromscreening libraries and for their exclusion in bioassaysrdquoJournal of Medicinal Chemistry vol 53 no 7 pp 2719ndash27402010

[47] T J Ritchie P Ertl and R Lewis ldquo)e graphical represen-tation of ADME-related molecule properties for medicinalchemistsrdquo Drug Discovery Today vol 16 no 1-2 pp 65ndash722011

[48] Z M Dastjerdi F Namjoyan and M E Azemi ldquoAlphaamylase inhibition activity of some plants extract of Teucriumspeciesrdquo European Journal of Biological Sciences vol 7pp 26ndash31 2015

[49] I M E Lacroix and E C Y Li-Chan ldquoOverview of foodproducts and dietary constituents with antidiabetic propertiesand their putative mechanisms of action a natural approachto complement pharmacotherapy in the management of di-abetesrdquo Molecular Nutrition amp Food Research vol 58 no 1pp 61ndash78 2014

[50] H V Rupasinghe S Sekhon-Loodu T Mantso andM I Panayiotidis ldquoPhytochemicals in regulating fatty acidβ-oxidation Potential underlying mechanisms and their in-volvement in obesity and weight lossrdquo Pharmacology ampEerapeutics vol 165 pp 153ndash163 2016

[51] M Qasim Z Abideen M Y Adnan et al ldquoAntioxidantproperties phenolic composition bioactive compounds andnutritive value of medicinal halophytes commonly used asherbal teasrdquo South African Journal of Botany vol 110pp 240ndash250 2017

[52] B Romano E Pagano V Montanaro A L FortunatoNMilic and F Borrelli ldquoNovel insights into the pharmacologyof flavonoidsrdquo Phytotherapy Research vol 27 pp 1588ndash15962013

[53] A P Rauter A Martins C Borges et al ldquoAntihyperglycaemicand protective effects of flavonoids on streptozotocinndashinduceddiabetic ratsrdquo Phytotherapy Research vol 24 pp S133ndashS1382010

[54] M O Agbo P F Uzor U N Nneji C U OdurukweU B Ogbatue and E C Mbaoji ldquoAntioxidant total phenolicand flavonoid content of selected Nigerian medicinal plantsrdquoDhaka University Journal of Pharmaceutical Science vol 14pp 35ndash41 2015

[55] N Saeed M R Khan and M Shabbir ldquoAntioxidant activitytotal phenolic and total flavonoid contents of whole plantextracts Torilis leptophylla Lrdquo BMC Complementary andAlternative Medicine vol 12 no 1 p 221 2012

[56] M R Kumbhare V Guleha and T Sivakumar ldquoEstimationof total phenolic content cytotoxicity and inndashvitro

antioxidant activity of stem bark of Moringa oleiferardquo AsianPacific Journal of Tropical Disease vol 2 pp 144ndash150 2012

[57] A A Ala B B Olotu and C M D Ohia ldquoAssessment ofcytotoxicity of leaf extracts of andrographis paniculata andaspilia Africana onmurine cellsrdquoArchives of basic and appliedmedicine vol 6 pp 61ndash65 2018

[58] S K Doreddula S R Bonam D P Gaddam B S R DesuN Ramarao and V Pandy ldquoPhytochemical analysis antioxi-dant antistress and nootropic activities of aqueous andmethanolic seed extracts of ladies finger (Abelmoschus escu-lentus L) in micerdquo Ee Scientific World Journal vol 2014Article ID 519848 14 pages 2014

[59] L A Nistor Baldea L C Martineau A Benhaddou-Anda-loussi J T Arnason E Levy and P S Haddad ldquoInhibition ofintestinal glucose absorption by anti-diabetic medicinal plantsderived from the James Bay Cree traditional pharmacopeiardquoJournal of Ethnopharmacology vol 132 no 2 pp 473ndash4822010

[60] N Shehzadi K Hussain N I Bukhari et al ldquoHypoglycemichepatoprotective and molecular docking studies of 5-[(4-chlorophenoxy) methyl]-1 3 4- oxadiazole-2-thiolrdquo Ban-gladesh Journal of Pharmacology vol 13 no 2 pp 149ndash1562018

[61] D Seeliger B L de Groot and V De Pymol ldquoLigand dockingand binding site analysis with PyMOL and AutodockVinardquoJournal of Computer-Aided Molecular Design vol 24pp 417ndash422 2010

[62] W Benalla S Bellahcen and M Bnouham ldquoAntidiabeticmedicinal plants as a source of alpha glucosidase inhibitorsrdquoCurrent Diabetes Reviews vol 6 no 4 pp 247ndash254 2010

[63] R Andleeb M U Ijaz A Rafique et al ldquoBiological activitiesof methanolic extract of aegle marmelos against HN protein ofnewcastle disease virusrdquo Agronomy vol 11 no 9 p 17842021

Evidence-Based Complementary and Alternative Medicine 17

Toxicity is an important factor in the design of phar-maceutical drugs and an important starting point for he-molytic actions providing principal knowledge on theinteraction at the cellular level between biological entitiesand molecules Hemolytic activity of any compound is a signof common cytotoxicity towards normal healthy cells In thisresearch MEAE exhibited 10 cytotoxicity toward humanerythrocytes as shown in Table 3 Such findings demonstratethat if medicinal formulations from this plant are used at lowconcentrations parameters of the RBC membrane will notchange Reports on the toxic effects of A esculentus areinsufficient A previous study conducted with aqueous andmethanolic extracts of the A esculentus fruit confirmed thatthere were no deaths up to a dose of 2000mgkg (po) inSwiss mice (n 6) for 7 days and no signs of toxicity [58]which may be one of the significant issues for considering itas an important vegetable for human use Further research isessential on this medicinal edible plant in the context of drugdevelopment and discovery

Dietary phenols and flavonoids in accumulation totheir antioxidant effects have been noticed to exert anti-hyperglycemic effects by binding to the transporters of

glucose [49] and spirited digestive enzyme inhibition [59])e carbohydrate-digesting enzymes α-glucosidase andα-amylase digest dietary starch and produce glucoseresulting in surge of postprandial glucose So the inhibition ofα-glucosidase and α-amylase activities is one of the primaryapproaches to managing hyperglycemic T2D patients

T divaricata has antidiabetic activity according to al-pha-amylase inhibitory tests )e percentage inhibitoryactivity of plant methanolic extract against alpha-amylaseenzyme increased in a dose-dependent manner )e plantextract concentration of 50 gml showed a percentage in-hibition of 28 while 200 gml showed a percentage inhi-bition of 61 At a high concentration of 200 gml theextract inhibited the alpha-amylase enzyme by 50 As aresult of the current inhibitory studies it has been discoveredthat the T divaricata plant extract is successful in inhibitingthe alpha-amylase enzyme which helps to postpone thebreakdown of starch into glucose and thus maintain glucoselevels in diabetic patients Dastjerdi et al [48] observedα-amylase inhibition activity of some plant extracts of Teucrium species values ranged from 4159plusmn 064 to7707plusmn 049 at 156mgmL to 25mgmL )e α-amylase

Table 8 Docking interactions of different active compounds of T divaricate

Compound Goldscore

Gold bindingfitness RMSD Residue Hydrophobicity Pka Distance

2-phenylthiolane 0205 2914 7861

LEU777 38 476ARG779 minus45 12 384VAL784 42 492LEU846 38 509

4-(4-Methyl-2-biphenylyloxy) phthalonitrile minus653 3721 6918

LEU777 38 457ARG779 minus45 12 47ASN780 minus35 319THR782 minus07 234VAL784 42 508LEU846 38 220

Cyclohexanepropanoic acid 3-oxo- methyl ester minus093 2829 6543 ARG779 minus45 12 226VAL784 42 442

Cyclopropane tetradecanoic acid 2-octyl- methylester minus751 3928 6909

LEU777 38 532ARG779 minus45 12 461VAL784 42 502LEU815 38 508SER848 minus08 247TRP849 minus09 264CYS850 25 9 374

1610-Dodecatriene 711-dimethyl-3-methylene- minus403 3269 6703LEU777 38 513ARG779 minus45 12 499VAL784 42 388

N-Methylallylamine minus016 2000 6588

LEU777 38 408ARG779 minus45 12 370THR782 minus07 152VAL784 42 484

Propanamide minus059 1916 6542LEU777 38 220THR782 minus07 286VAL784 42 528

1H-Tetrazol-5-amine 000 1721 6678GLU750 minus35 43 259ARG779 minus45 12 185ASN780 minus35 274

Cyclohexene 3-ethenyl 014 2383 6450LEU777 38 497ARG779 minus45 12 389VAL784 42 435

12 Evidence-Based Complementary and Alternative Medicine

N-Methylallylamine

Interactions

Conventional Hydrogen Bond

Alkyl

Phthalonitrile

Interactions

Unfavorable Bump

Pi-Donor Hydrogen Bond

Alkyl

Pi-Alkyl

Cyclopropane tetradecanoic acid2-octyl- methyl ester

Interactions

Conventional Hydrogen Bond

Corbon Hydrogen Bond

Alkyl

1H-Tetrazol-5-amine

Interactions

Conventional Hydrogen Bond

Pi-Sigma

Pi-Alkyl

Cyclohexanepropanoic acid

Interactions

Conventional Hydrogen Bond

Alkyl

Cyclohexene 3-ethenyl

Interactions

Alkyl

(a)

Figure 3 Continued

Evidence-Based Complementary and Alternative Medicine 13

inhibitory activity of methanol plant extract is most likely bypolar compounds that should be investigated further byisolating pure active compounds

At 50ndash200 gml concentrations of T divaricata ex-tract the percentage inhibition increased in a dose-de-pendent manner For the highest and lowestconcentrations respectively the percentage inhibitionranged from 60 to 31 (Table 4) )us by inhibiting thealpha-glucosidase enzyme the extract of T divaricatawhich contains various natural bioactive compoundshelps to reduce the rate of carbohydrate digestionlowering blood glucose levels and maintaining diabeticconditions

Glucose uptake is one of the in vitro methods used toexplore the antihyperglycemic effect of different compounds[60] )e average values of glucose uptake by yeast cells inthis study were 1305plusmn 13 to 695plusmn 478 Shehzadi et al[60] reported the evaluation of antihyperglycemic activitythrough in vitro assays (02 to 263) at 2mgmL which wasbelow the current research values )e results indicated allused concentrations under examination are capable of in-creasing the utilization and uptake of glucose in yeast cells

)e in silico prediction of molecular physicochemicalparameters bioavailability and the pharmacokinetics havebecome more relevant for the investigation of productivepotential drug molecules from a drug discovery standpoint[47] )eoretical experiments play a critical role in presentingaccurate data in a timely and comfortable manner Many freeonline platforms have recently been established for fasterscreening reducing the time and expense of drug testing (noanimal testing) [46] SwissADME is a modern comprehensivemethod developed by the Swiss Institute of Bioinformatics(SIB) that allows drug candidates to have their absorptiondelivery metabolism and excretion (ADME) parametersestimated [45] At the outset of the drug development processADME properties which determine either the potentialdrugrsquos access to the target or its removal by the organism arethe required properties that must be evaluated for the drug tobe selected In silico experiments based on measured phys-icochemical requirements can be used to check these pa-rameters SwissADME also provides information ongastrointestinal absorption (GIA) and blood-brain barrier(BBB) permeability in humans From twenty-six selectedcompounds only eight compounds fulfilled the criteria of

1 6 10-Dodecatriene 7 11-dimethyl-3-methylene

Interactions

Alkyl

2-phenylthiolane Propanamide

Interactions

Alkyl

Pi-Alkyl

Propanamide

Interactions

Conventional Hydrogen Bond

Alkyl

(b)

Figure 3 In silico molecular docking results of interactions between 5kzw proteins with screened compounds as ligand

14 Evidence-Based Complementary and Alternative Medicine

drug-likeness parameters So all of these nine compoundswere further processed for molecular docking by GOLD

To predict the affinity and behavior of small moleculesand drug candidates computational molecular docking iscommonly used to predict the binding orientation to theirprotein targets [61] We used molecular docking to modelvarious bioactive compounds isolated from the Jasmineplant that is known to inhibit glucosidase Because of theirlow price and comparatively greater protection with a lowfrequency of severe gastrointestinal side effects plants orplant-based substances may be a suitable source of gluco-sidase inhibitors [62] Hydrogen bonds play a crucial role inthe structure and interaction of protein-protein or ligand-receptor complexes Hydrogen bonds are important in drugdesign to ensure that the drug is unique to the protein targetTo back up the findings of this research a molecular dockingstudy was performed (cyclopropane tetradecanoic acid 2-octyl- methyl ester 4-(4-methyl-2-biphenylyloxy) phtha-lonitrile) which showed excellent interaction with 5kzwprotein having Gold fitness (3928 3721) and GOLDdocking score of -751 and -653 including the formation ofhydrogen bond with amino acids residues (1610-dodeca-triene 711-dimethyl-3-methylene 2-phenylthiolane andcyclohexane propanoic acid 3-oxo- methyl ester) )esemolecules showed exceptionally good interaction withα-glucosidase protein and can be considered as potentialmolecules that may prove to be beneficial in antiviral activitythrough their direct action on new castle disease [63] )esecompounds showed moderate binding affinity of 32692914 and 2829 and GOLD docking scores of -403 0205and 093 respectively N-methylallylamine propanamidecyclohexene and 3-ethenyl have the least interaction in therange of 2000 1916 and 2383 and docking scores of -016-059 and 014 while 1H-tetrazol-5-amine compoundshowed the least affinity towards 5kzw binding site

5 Conclusion

Since diabetes mellitus is a global epidemic effective drugswith less or no toxicity must be developed and one such wayis the use of herbal medicines having no side effects )isstudy investigated the antidiabetic and antioxidant prop-erties of T divaricata extract and found promising inhibitorsof two carbohydrate-related enzymes T divaricata has richphenolic and flavonoid contents As a flavonoid it has greatantidiabetic potential and also causes active uptake of glu-cose )e methanolic extract of T divaricate has great po-tential for stimulation of α-amylase and α-glucosidase sothat it can be used to treat diabetes In silico docking studiesof phytoactive compounds from T divaricata have beenproven to have potential drug capabilities in terms of theirpharmacokinetic and drug-likeness )e molecular dockinganalysis described some compounds that inhibited thetargets related to diabetes mellitus and showed encouragingresults with prominent inhibitory activity )is study showsthat T divaricata extract which is rich in important bio-active compounds can be used for diabetes It is suggested tocarry out long-term research work to recognize and isolatethe active moieties responsible for antidiabetic property and

to understand the mechanisms involved in glucose-loweringproperties of the plant

Data Availability

Data are available from authors on reasonable demand

Conflicts of Interest

)e authors declare that there are no conflicts of interestregarding the publication of this study

Acknowledgments

)e facilities and support provided by the Department ofZoology Government College University Faisalabad arehighly acknowledged

References

[1] C D Deshmukh and A Jain ldquoDiabetes mellitus a reviewrdquoInternational Journal of Pure and Applied Biosciences vol 3pp 224ndash230 2015

[2] American Diabetes Association (ADA) ldquo5 Lifestyle man-agement Standards of medical care in diabetesmdash2019rdquo Di-abetes Care vol 42 no 1 pp S46ndashS60 2019

[3] A Meeinta C Rojwipaporn R Chanaporn et al ldquoDiabetesmellitus HbA1c and lung function do they are relatedrdquo Di-abetes amp its Complications vol 2 no 3 pp 1ndash6 2018

[4] U Yoon L L Kwok and A Magkidis ldquoEfficacy of lifestyleinterventions in reducing diabetes incidence in patients withimpaired glucose tolerance a systematic review of random-ized controlled trialsrdquo BMC Proceedings vol 6 pp P28ndashP142012

[5] S B Aynalem and A J Zeleke ldquoPrevalence of diabetesmellitus and its risk factors among individuals aged 15 yearsand above in Mizan-Aman town a cross sectional studyrdquoInternational Journal of Endocrinology vol 2018 Article ID9317987 7 pages 2018

[6] D R Whiting L Guariguata C Weil and J Shaw ldquoIDFdiabetes atlas global estimates of the prevalence of diabetesfor 2011 and 2030rdquo Diabetes Research and Clinical Practicevol 94 pp 311ndash321 2011

[7] P Agarwal and R Gupta ldquoAlpha-amylase inhibition can treatdiabetes mellitusrdquo Research Review Journal of Medical HealthScience vol 5 pp 1ndash8 2016

[8] H Kaneto N Katakami M Matsuhisa and T A MatsuokaldquoRole of reactive oxygen species in the progression of type 2diabetes and atherosclerosisrdquo Mediators of Inflammationvol 2010 Article ID 453892 11 pages 2010

[9] Z Sun and R Albert ldquoBoolean models of cellular signalingnetworksrdquo in Handbook of Systems BiologyElsevier Amster-dam Netherlands 2013

[10] M Nazıroglu ldquoNew molecular mechanisms on the activationof TRPM2 channels by oxidative stress and ADP-riboserdquoNeurochemical Research vol 32 pp 1990ndash2001 2007

[11] R Dringen ldquoOxidative and antioxidative potential of brainmicroglial cellsrdquo Antioxidants and Redox Signaling vol 7pp 1223ndash1233 2005

[12] T Zahidi A Lekchiri T Zahidi W Lekchiri and A BerrichialdquoExtraction and comparison of two new peroxidases fromleaves and roots of Brassica oleraceae var ramoserdquo Journal of

Evidence-Based Complementary and Alternative Medicine 15

Materials and Environmental Science vol 9 pp 1398ndash14042018

[13] D M Kasote S S Katyare M V Hegde and H BaeldquoSignificance of antioxidant potential of plants and its rele-vance to therapeutic applicationsrdquo International Journal ofBiological Sciences vol 11 pp 982ndash991 2015

[14] W Kooti M Farokhipour Z Asadzadeh D Ashtary-Larkyand M Asadi-Samani ldquo)e role of medicinal plants in thetreatment of diabetes a systematic reviewrdquo Electronic Phy-sician vol 8 no 1 pp 1832ndash1842 2016

[15] M S Aslam and M S Ahmad ldquoWorldwide importance ofmedicinal plants current and historical perspectivesrdquo RecentAdvances in Biology and Medicine vol 02 p 88 2016

[16] S Ponnusamy R Ravindran S Zinjarde S Bhargava andA R Kumar ldquoEvaluation of traditional Indian antidiabeticmedicinal plants for human pancreatic amylase inhibitoryeffect in vitrordquo Evidence-Based Complementary and Alter-native Medicine vol 2011 Article ID 515647 10 pages 2011

[17] P P Bijeshmon and S George ldquoAntimicrobial activity andpowder microscopy of the flowers of Tabernaemontanadivaricata Rrdquo BRrdquo Indo American Journal of PharmaceuticalResearch vol 4 pp 1601ndash1605 2014

[18] V L Singleton R Orthofer and R M Lamuela-RaventosldquoAnalysis of total phenols and other oxidation substrates andantioxidants by means of folin-ciocalteu reagentrdquoMethods inEnzymology vol 299 pp 152ndash178 1999

[19] J Bao Y Cai M Sun G Wang and H Corke ldquoAnthocy-anins flavonols and free radical scavenging activity of Chi-nese bayberry (Myrica rubra) extracts and their colorproperties and stabilityrdquo Journal of Agricultural and FoodChemistry vol 53 pp 2327ndash2332 2005

[20] M Mohebbi-Fani A Mirzaei S Nazifi and M R TabandehldquoOxidative status and antioxidant enzyme activities inerythrocytes from breeding and pregnant ewes grazing nat-ural pastures in dry seasonrdquo Revue de Medecine Veterinairevol 163 pp 454ndash460 2012

[21] G H Onsa N bin Saari J Selamat and J Bakar ldquoPurificationand characterization of membrane-bound peroxidases fromMetroxylon sagurdquo Food Chemistry vol 85 no 3 pp 365ndash3762004

[22] M Kumar A J Bijo R S Baghel C Reddy and B JhaldquoSelenium and spermine alleviate cadmium induced toxicityin the red seaweed Gracilaria dura by regulating antioxidantsand DNA methylationrdquo Plant Physiology and Biochemistryvol 51 pp 129ndash138 2012

[23] W A Powell C M Catranis and C A Maynard ldquoDesign ofself-processing antimicrobial peptides for plant protectionrdquoLetters in Applied Microbiology vol 31 pp 163ndash168 2000

[24] L J Shai P Masoko M P Mokgotho et al ldquoYeast alphaglucosidase inhibitory and antioxidant activities of six me-dicinal plants collected in Phalaborwa South Africardquo SouthAfrican Journal of Botany vol 76 pp 465ndash470 2010

[25] A O Ademiluyi and G Oboh ldquoSoybean phenolic-rich extractsinhibit key-enzymes linked to type 2 diabetes (α-amylase andα-glucosidase) and hypertension (angiotensin I convertingenzyme) in vitrordquo Experimental amp Toxicologic Pathologyvol 65 pp 305ndash309 2013

[26] V P Cirillo ldquoMechanism of glucose transport across the yeastcell membranerdquo Journal of Bacteriology vol 84 pp 485ndash4911962

[27] C Kalaimagal ldquoIdentification of bioactive compounds inflower of Tabernaemontana divaricata (l) using gas chro-matographyndashmass spectrometry analysisrdquo Asian Journal of

Pharmaceutical and Clinical Research vol 12 pp 129ndash1322019

[28] H H Rassem A Hamid Nour and R Mohamed YunusldquoAnalysis of bioactive compounds for Jasmine flower via Gaschromatography-mass spectrometry (GC-MS)rdquo MalaysianJournal of Fundamental and Applied Sciences vol 14 no 2pp 198ndash201 2018

[29] M S Ali Khan AMMat Jais and A Afreen ldquoAnalogous andantioxidant activity mediated gastroprotective action ofTabernaemontana divaricata (L) R Br flower methanolicextract against chemically induced gastric ulcers in ratsrdquoBioMed Research International vol 2013 Article ID 18547618 pages 2013

[30] D F Veber S R Johnson H Y Cheng B R SmithK W Ward and K D Kopple ldquoMolecular properties thatinfluence the oral bioavailability of drug candidatesrdquo Journalof Medicinal Chemistry vol 45 no 12 pp 2615ndash2623 2002

[31] C A Lipinski A Lombardo B W Dominy F Dominy andP J Feeney ldquoExperimental and computational approaches toestimate solubility and permeability in drug discovery anddevelopment settingsrdquo Advanced Drug Delivery Reviewsvol 46 pp 3ndash26 2001

[32] A K Ghose V N Viswanadhan and J J Wendoloski ldquoAknowledge-based approach in designing combinatorial ormedicinal chemistry libraries for drug discovery 1 A qualitativeand quantitative characterization of known drug databasesrdquoJournal of Combinatorial Chemistry vol 1 pp 55ndash68 1999

[33] Z Bikadi and E Hazai ldquoApplication of the PM6 semi-em-pirical method to modeling proteins enhances docking ac-curacy of AutoDockrdquo Journal of Cheminformatics vol 1p 15 2009

[34] S S Azam A Saroosh N Zaman and S Raza ldquoRole ofN-acetylserotonin O-methyltransferase in bipolar disordersand its dynamicsrdquo Journal of Molecular Liquids vol 182pp 25ndash31 2013

[35] O Trott and A J Olson ldquoAutoDockVina improving thespeed and accuracy of docking with a new scoring functionefficient optimization and multi-threadingrdquo Journal ofComputational Chemistry vol 31 pp 455ndash461 2010

[36] G M Morris D S Goodsell R S Halliday et al ldquoAutomateddocking using a Lamarckian genetic algorithm and an em-pirical binding free energy functionrdquo Journal of Computa-tional Chemistry vol 19 no 14 pp 1639ndash1662 1998

[37] T A Halgren ldquoCharacterization of MMFF94 MMFF94s andother widely available force fields for conformational energiesand for intermolecular-interaction energies and geometriesrdquoJournal of Computational Chemistry vol 20 1999

[38] C Y Chung H Y Chung W T Sung et al ldquoMoleculardocking for protein folding structure and drug-likenessprediction WSEAS conferencerdquo International Journal ofBiology and Biomedicine vol 1 pp 57ndash63 2005

[39] G Li H Zhou Y Jiang et al ldquoDesign and synthesis of 4-arylpiperidinyl amide and N-arylpiperdin-3-yl-cyclopropanecarboxamide derivatives as novel melatonin receptor ligandsrdquoBioorganic amp Medicinal Chemistry Letters vol 21 no 4pp 1236ndash1242 2011

[40] F J Solis and R J B Wets ldquoMinimization by random searchtechniquesrdquoMathematics of Operations Research vol 6 no 1pp 19ndash30 1981

[41] I A Alswaidan K Sooknah L Rhyman et al ldquo2 4-Ditel-lurouracil and its 5-fluoro derivative )eoretical investiga-tions of structural energetics and ADME parametersrdquoComputational Biology and Chemistry vol 68 pp 56ndash632017

16 Evidence-Based Complementary and Alternative Medicine

[42] M F Fromm ldquoP-glycoprotein a defense mechanism limitingoral bioavailability and CNS accumulation of drugsrdquo Inter-national Journal of Clinical Pharmacology amp Eerapeuticsvol 38 no 2 pp 69ndash74 2000

[43] G Szakacs A Varadi C Ozvegy Laczka and B Sarkadi ldquo)erole of ABC transporters in drug absorption distributionmetabolism excretion and toxicity (ADME-Tox)rdquo Drug Dis-covery Today vol 13 no 9-10 pp 379ndash393 2008

[44] B Testa and S D Kraemer ldquo)e biochemistry of drugmetabolism an introduction part 2 Redox reactions and theirenzymesrdquo ChemInform vol 38 no 23 pp 257ndash405 2007

[45] S Meeran V Baskar S Syed Tajudeen and T K ShabeerldquoDesign ADME profiling and molecular docking simulationof new isoniazid schiff base analogs as MtKasB InhibitorsrdquoAsian Journal of Chemistry and Pharmaceutical Science vol 6pp 20ndash34 2018

[46] J B Baell and G A Holloway ldquoNew substructure filters forremoval of pan assay interference compounds (PAINS) fromscreening libraries and for their exclusion in bioassaysrdquoJournal of Medicinal Chemistry vol 53 no 7 pp 2719ndash27402010

[47] T J Ritchie P Ertl and R Lewis ldquo)e graphical represen-tation of ADME-related molecule properties for medicinalchemistsrdquo Drug Discovery Today vol 16 no 1-2 pp 65ndash722011

[48] Z M Dastjerdi F Namjoyan and M E Azemi ldquoAlphaamylase inhibition activity of some plants extract of Teucriumspeciesrdquo European Journal of Biological Sciences vol 7pp 26ndash31 2015

[49] I M E Lacroix and E C Y Li-Chan ldquoOverview of foodproducts and dietary constituents with antidiabetic propertiesand their putative mechanisms of action a natural approachto complement pharmacotherapy in the management of di-abetesrdquo Molecular Nutrition amp Food Research vol 58 no 1pp 61ndash78 2014

[50] H V Rupasinghe S Sekhon-Loodu T Mantso andM I Panayiotidis ldquoPhytochemicals in regulating fatty acidβ-oxidation Potential underlying mechanisms and their in-volvement in obesity and weight lossrdquo Pharmacology ampEerapeutics vol 165 pp 153ndash163 2016

[51] M Qasim Z Abideen M Y Adnan et al ldquoAntioxidantproperties phenolic composition bioactive compounds andnutritive value of medicinal halophytes commonly used asherbal teasrdquo South African Journal of Botany vol 110pp 240ndash250 2017

[52] B Romano E Pagano V Montanaro A L FortunatoNMilic and F Borrelli ldquoNovel insights into the pharmacologyof flavonoidsrdquo Phytotherapy Research vol 27 pp 1588ndash15962013

[53] A P Rauter A Martins C Borges et al ldquoAntihyperglycaemicand protective effects of flavonoids on streptozotocinndashinduceddiabetic ratsrdquo Phytotherapy Research vol 24 pp S133ndashS1382010

[54] M O Agbo P F Uzor U N Nneji C U OdurukweU B Ogbatue and E C Mbaoji ldquoAntioxidant total phenolicand flavonoid content of selected Nigerian medicinal plantsrdquoDhaka University Journal of Pharmaceutical Science vol 14pp 35ndash41 2015

[55] N Saeed M R Khan and M Shabbir ldquoAntioxidant activitytotal phenolic and total flavonoid contents of whole plantextracts Torilis leptophylla Lrdquo BMC Complementary andAlternative Medicine vol 12 no 1 p 221 2012

[56] M R Kumbhare V Guleha and T Sivakumar ldquoEstimationof total phenolic content cytotoxicity and inndashvitro

antioxidant activity of stem bark of Moringa oleiferardquo AsianPacific Journal of Tropical Disease vol 2 pp 144ndash150 2012

[57] A A Ala B B Olotu and C M D Ohia ldquoAssessment ofcytotoxicity of leaf extracts of andrographis paniculata andaspilia Africana onmurine cellsrdquoArchives of basic and appliedmedicine vol 6 pp 61ndash65 2018

[58] S K Doreddula S R Bonam D P Gaddam B S R DesuN Ramarao and V Pandy ldquoPhytochemical analysis antioxi-dant antistress and nootropic activities of aqueous andmethanolic seed extracts of ladies finger (Abelmoschus escu-lentus L) in micerdquo Ee Scientific World Journal vol 2014Article ID 519848 14 pages 2014

[59] L A Nistor Baldea L C Martineau A Benhaddou-Anda-loussi J T Arnason E Levy and P S Haddad ldquoInhibition ofintestinal glucose absorption by anti-diabetic medicinal plantsderived from the James Bay Cree traditional pharmacopeiardquoJournal of Ethnopharmacology vol 132 no 2 pp 473ndash4822010

[60] N Shehzadi K Hussain N I Bukhari et al ldquoHypoglycemichepatoprotective and molecular docking studies of 5-[(4-chlorophenoxy) methyl]-1 3 4- oxadiazole-2-thiolrdquo Ban-gladesh Journal of Pharmacology vol 13 no 2 pp 149ndash1562018

[61] D Seeliger B L de Groot and V De Pymol ldquoLigand dockingand binding site analysis with PyMOL and AutodockVinardquoJournal of Computer-Aided Molecular Design vol 24pp 417ndash422 2010

[62] W Benalla S Bellahcen and M Bnouham ldquoAntidiabeticmedicinal plants as a source of alpha glucosidase inhibitorsrdquoCurrent Diabetes Reviews vol 6 no 4 pp 247ndash254 2010

[63] R Andleeb M U Ijaz A Rafique et al ldquoBiological activitiesof methanolic extract of aegle marmelos against HN protein ofnewcastle disease virusrdquo Agronomy vol 11 no 9 p 17842021

Evidence-Based Complementary and Alternative Medicine 17

N-Methylallylamine

Interactions

Conventional Hydrogen Bond

Alkyl

Phthalonitrile

Interactions

Unfavorable Bump

Pi-Donor Hydrogen Bond

Alkyl

Pi-Alkyl

Cyclopropane tetradecanoic acid2-octyl- methyl ester

Interactions

Conventional Hydrogen Bond

Corbon Hydrogen Bond

Alkyl

1H-Tetrazol-5-amine

Interactions

Conventional Hydrogen Bond

Pi-Sigma

Pi-Alkyl

Cyclohexanepropanoic acid

Interactions

Conventional Hydrogen Bond

Alkyl

Cyclohexene 3-ethenyl

Interactions

Alkyl

(a)

Figure 3 Continued

Evidence-Based Complementary and Alternative Medicine 13

inhibitory activity of methanol plant extract is most likely bypolar compounds that should be investigated further byisolating pure active compounds

At 50ndash200 gml concentrations of T divaricata ex-tract the percentage inhibition increased in a dose-de-pendent manner For the highest and lowestconcentrations respectively the percentage inhibitionranged from 60 to 31 (Table 4) )us by inhibiting thealpha-glucosidase enzyme the extract of T divaricatawhich contains various natural bioactive compoundshelps to reduce the rate of carbohydrate digestionlowering blood glucose levels and maintaining diabeticconditions

Glucose uptake is one of the in vitro methods used toexplore the antihyperglycemic effect of different compounds[60] )e average values of glucose uptake by yeast cells inthis study were 1305plusmn 13 to 695plusmn 478 Shehzadi et al[60] reported the evaluation of antihyperglycemic activitythrough in vitro assays (02 to 263) at 2mgmL which wasbelow the current research values )e results indicated allused concentrations under examination are capable of in-creasing the utilization and uptake of glucose in yeast cells

)e in silico prediction of molecular physicochemicalparameters bioavailability and the pharmacokinetics havebecome more relevant for the investigation of productivepotential drug molecules from a drug discovery standpoint[47] )eoretical experiments play a critical role in presentingaccurate data in a timely and comfortable manner Many freeonline platforms have recently been established for fasterscreening reducing the time and expense of drug testing (noanimal testing) [46] SwissADME is a modern comprehensivemethod developed by the Swiss Institute of Bioinformatics(SIB) that allows drug candidates to have their absorptiondelivery metabolism and excretion (ADME) parametersestimated [45] At the outset of the drug development processADME properties which determine either the potentialdrugrsquos access to the target or its removal by the organism arethe required properties that must be evaluated for the drug tobe selected In silico experiments based on measured phys-icochemical requirements can be used to check these pa-rameters SwissADME also provides information ongastrointestinal absorption (GIA) and blood-brain barrier(BBB) permeability in humans From twenty-six selectedcompounds only eight compounds fulfilled the criteria of

1 6 10-Dodecatriene 7 11-dimethyl-3-methylene

Interactions

Alkyl

2-phenylthiolane Propanamide

Interactions

Alkyl

Pi-Alkyl

Propanamide

Interactions

Conventional Hydrogen Bond

Alkyl

(b)

Figure 3 In silico molecular docking results of interactions between 5kzw proteins with screened compounds as ligand

14 Evidence-Based Complementary and Alternative Medicine

drug-likeness parameters So all of these nine compoundswere further processed for molecular docking by GOLD

To predict the affinity and behavior of small moleculesand drug candidates computational molecular docking iscommonly used to predict the binding orientation to theirprotein targets [61] We used molecular docking to modelvarious bioactive compounds isolated from the Jasmineplant that is known to inhibit glucosidase Because of theirlow price and comparatively greater protection with a lowfrequency of severe gastrointestinal side effects plants orplant-based substances may be a suitable source of gluco-sidase inhibitors [62] Hydrogen bonds play a crucial role inthe structure and interaction of protein-protein or ligand-receptor complexes Hydrogen bonds are important in drugdesign to ensure that the drug is unique to the protein targetTo back up the findings of this research a molecular dockingstudy was performed (cyclopropane tetradecanoic acid 2-octyl- methyl ester 4-(4-methyl-2-biphenylyloxy) phtha-lonitrile) which showed excellent interaction with 5kzwprotein having Gold fitness (3928 3721) and GOLDdocking score of -751 and -653 including the formation ofhydrogen bond with amino acids residues (1610-dodeca-triene 711-dimethyl-3-methylene 2-phenylthiolane andcyclohexane propanoic acid 3-oxo- methyl ester) )esemolecules showed exceptionally good interaction withα-glucosidase protein and can be considered as potentialmolecules that may prove to be beneficial in antiviral activitythrough their direct action on new castle disease [63] )esecompounds showed moderate binding affinity of 32692914 and 2829 and GOLD docking scores of -403 0205and 093 respectively N-methylallylamine propanamidecyclohexene and 3-ethenyl have the least interaction in therange of 2000 1916 and 2383 and docking scores of -016-059 and 014 while 1H-tetrazol-5-amine compoundshowed the least affinity towards 5kzw binding site

5 Conclusion

Since diabetes mellitus is a global epidemic effective drugswith less or no toxicity must be developed and one such wayis the use of herbal medicines having no side effects )isstudy investigated the antidiabetic and antioxidant prop-erties of T divaricata extract and found promising inhibitorsof two carbohydrate-related enzymes T divaricata has richphenolic and flavonoid contents As a flavonoid it has greatantidiabetic potential and also causes active uptake of glu-cose )e methanolic extract of T divaricate has great po-tential for stimulation of α-amylase and α-glucosidase sothat it can be used to treat diabetes In silico docking studiesof phytoactive compounds from T divaricata have beenproven to have potential drug capabilities in terms of theirpharmacokinetic and drug-likeness )e molecular dockinganalysis described some compounds that inhibited thetargets related to diabetes mellitus and showed encouragingresults with prominent inhibitory activity )is study showsthat T divaricata extract which is rich in important bio-active compounds can be used for diabetes It is suggested tocarry out long-term research work to recognize and isolatethe active moieties responsible for antidiabetic property and

to understand the mechanisms involved in glucose-loweringproperties of the plant

Data Availability

Data are available from authors on reasonable demand

Conflicts of Interest

)e authors declare that there are no conflicts of interestregarding the publication of this study

Acknowledgments

)e facilities and support provided by the Department ofZoology Government College University Faisalabad arehighly acknowledged

References

[1] C D Deshmukh and A Jain ldquoDiabetes mellitus a reviewrdquoInternational Journal of Pure and Applied Biosciences vol 3pp 224ndash230 2015

[2] American Diabetes Association (ADA) ldquo5 Lifestyle man-agement Standards of medical care in diabetesmdash2019rdquo Di-abetes Care vol 42 no 1 pp S46ndashS60 2019

[3] A Meeinta C Rojwipaporn R Chanaporn et al ldquoDiabetesmellitus HbA1c and lung function do they are relatedrdquo Di-abetes amp its Complications vol 2 no 3 pp 1ndash6 2018

[4] U Yoon L L Kwok and A Magkidis ldquoEfficacy of lifestyleinterventions in reducing diabetes incidence in patients withimpaired glucose tolerance a systematic review of random-ized controlled trialsrdquo BMC Proceedings vol 6 pp P28ndashP142012

[5] S B Aynalem and A J Zeleke ldquoPrevalence of diabetesmellitus and its risk factors among individuals aged 15 yearsand above in Mizan-Aman town a cross sectional studyrdquoInternational Journal of Endocrinology vol 2018 Article ID9317987 7 pages 2018

[6] D R Whiting L Guariguata C Weil and J Shaw ldquoIDFdiabetes atlas global estimates of the prevalence of diabetesfor 2011 and 2030rdquo Diabetes Research and Clinical Practicevol 94 pp 311ndash321 2011

[7] P Agarwal and R Gupta ldquoAlpha-amylase inhibition can treatdiabetes mellitusrdquo Research Review Journal of Medical HealthScience vol 5 pp 1ndash8 2016

[8] H Kaneto N Katakami M Matsuhisa and T A MatsuokaldquoRole of reactive oxygen species in the progression of type 2diabetes and atherosclerosisrdquo Mediators of Inflammationvol 2010 Article ID 453892 11 pages 2010

[9] Z Sun and R Albert ldquoBoolean models of cellular signalingnetworksrdquo in Handbook of Systems BiologyElsevier Amster-dam Netherlands 2013

[10] M Nazıroglu ldquoNew molecular mechanisms on the activationof TRPM2 channels by oxidative stress and ADP-riboserdquoNeurochemical Research vol 32 pp 1990ndash2001 2007

[11] R Dringen ldquoOxidative and antioxidative potential of brainmicroglial cellsrdquo Antioxidants and Redox Signaling vol 7pp 1223ndash1233 2005

[12] T Zahidi A Lekchiri T Zahidi W Lekchiri and A BerrichialdquoExtraction and comparison of two new peroxidases fromleaves and roots of Brassica oleraceae var ramoserdquo Journal of

Evidence-Based Complementary and Alternative Medicine 15

Materials and Environmental Science vol 9 pp 1398ndash14042018

[13] D M Kasote S S Katyare M V Hegde and H BaeldquoSignificance of antioxidant potential of plants and its rele-vance to therapeutic applicationsrdquo International Journal ofBiological Sciences vol 11 pp 982ndash991 2015

[14] W Kooti M Farokhipour Z Asadzadeh D Ashtary-Larkyand M Asadi-Samani ldquo)e role of medicinal plants in thetreatment of diabetes a systematic reviewrdquo Electronic Phy-sician vol 8 no 1 pp 1832ndash1842 2016

[15] M S Aslam and M S Ahmad ldquoWorldwide importance ofmedicinal plants current and historical perspectivesrdquo RecentAdvances in Biology and Medicine vol 02 p 88 2016

[16] S Ponnusamy R Ravindran S Zinjarde S Bhargava andA R Kumar ldquoEvaluation of traditional Indian antidiabeticmedicinal plants for human pancreatic amylase inhibitoryeffect in vitrordquo Evidence-Based Complementary and Alter-native Medicine vol 2011 Article ID 515647 10 pages 2011

[17] P P Bijeshmon and S George ldquoAntimicrobial activity andpowder microscopy of the flowers of Tabernaemontanadivaricata Rrdquo BRrdquo Indo American Journal of PharmaceuticalResearch vol 4 pp 1601ndash1605 2014

[18] V L Singleton R Orthofer and R M Lamuela-RaventosldquoAnalysis of total phenols and other oxidation substrates andantioxidants by means of folin-ciocalteu reagentrdquoMethods inEnzymology vol 299 pp 152ndash178 1999

[19] J Bao Y Cai M Sun G Wang and H Corke ldquoAnthocy-anins flavonols and free radical scavenging activity of Chi-nese bayberry (Myrica rubra) extracts and their colorproperties and stabilityrdquo Journal of Agricultural and FoodChemistry vol 53 pp 2327ndash2332 2005

[20] M Mohebbi-Fani A Mirzaei S Nazifi and M R TabandehldquoOxidative status and antioxidant enzyme activities inerythrocytes from breeding and pregnant ewes grazing nat-ural pastures in dry seasonrdquo Revue de Medecine Veterinairevol 163 pp 454ndash460 2012

[21] G H Onsa N bin Saari J Selamat and J Bakar ldquoPurificationand characterization of membrane-bound peroxidases fromMetroxylon sagurdquo Food Chemistry vol 85 no 3 pp 365ndash3762004

[22] M Kumar A J Bijo R S Baghel C Reddy and B JhaldquoSelenium and spermine alleviate cadmium induced toxicityin the red seaweed Gracilaria dura by regulating antioxidantsand DNA methylationrdquo Plant Physiology and Biochemistryvol 51 pp 129ndash138 2012

[23] W A Powell C M Catranis and C A Maynard ldquoDesign ofself-processing antimicrobial peptides for plant protectionrdquoLetters in Applied Microbiology vol 31 pp 163ndash168 2000

[24] L J Shai P Masoko M P Mokgotho et al ldquoYeast alphaglucosidase inhibitory and antioxidant activities of six me-dicinal plants collected in Phalaborwa South Africardquo SouthAfrican Journal of Botany vol 76 pp 465ndash470 2010

[25] A O Ademiluyi and G Oboh ldquoSoybean phenolic-rich extractsinhibit key-enzymes linked to type 2 diabetes (α-amylase andα-glucosidase) and hypertension (angiotensin I convertingenzyme) in vitrordquo Experimental amp Toxicologic Pathologyvol 65 pp 305ndash309 2013

[26] V P Cirillo ldquoMechanism of glucose transport across the yeastcell membranerdquo Journal of Bacteriology vol 84 pp 485ndash4911962

[27] C Kalaimagal ldquoIdentification of bioactive compounds inflower of Tabernaemontana divaricata (l) using gas chro-matographyndashmass spectrometry analysisrdquo Asian Journal of

Pharmaceutical and Clinical Research vol 12 pp 129ndash1322019

[28] H H Rassem A Hamid Nour and R Mohamed YunusldquoAnalysis of bioactive compounds for Jasmine flower via Gaschromatography-mass spectrometry (GC-MS)rdquo MalaysianJournal of Fundamental and Applied Sciences vol 14 no 2pp 198ndash201 2018

[29] M S Ali Khan AMMat Jais and A Afreen ldquoAnalogous andantioxidant activity mediated gastroprotective action ofTabernaemontana divaricata (L) R Br flower methanolicextract against chemically induced gastric ulcers in ratsrdquoBioMed Research International vol 2013 Article ID 18547618 pages 2013

[30] D F Veber S R Johnson H Y Cheng B R SmithK W Ward and K D Kopple ldquoMolecular properties thatinfluence the oral bioavailability of drug candidatesrdquo Journalof Medicinal Chemistry vol 45 no 12 pp 2615ndash2623 2002

[31] C A Lipinski A Lombardo B W Dominy F Dominy andP J Feeney ldquoExperimental and computational approaches toestimate solubility and permeability in drug discovery anddevelopment settingsrdquo Advanced Drug Delivery Reviewsvol 46 pp 3ndash26 2001

[32] A K Ghose V N Viswanadhan and J J Wendoloski ldquoAknowledge-based approach in designing combinatorial ormedicinal chemistry libraries for drug discovery 1 A qualitativeand quantitative characterization of known drug databasesrdquoJournal of Combinatorial Chemistry vol 1 pp 55ndash68 1999

[33] Z Bikadi and E Hazai ldquoApplication of the PM6 semi-em-pirical method to modeling proteins enhances docking ac-curacy of AutoDockrdquo Journal of Cheminformatics vol 1p 15 2009

[34] S S Azam A Saroosh N Zaman and S Raza ldquoRole ofN-acetylserotonin O-methyltransferase in bipolar disordersand its dynamicsrdquo Journal of Molecular Liquids vol 182pp 25ndash31 2013

[35] O Trott and A J Olson ldquoAutoDockVina improving thespeed and accuracy of docking with a new scoring functionefficient optimization and multi-threadingrdquo Journal ofComputational Chemistry vol 31 pp 455ndash461 2010

[36] G M Morris D S Goodsell R S Halliday et al ldquoAutomateddocking using a Lamarckian genetic algorithm and an em-pirical binding free energy functionrdquo Journal of Computa-tional Chemistry vol 19 no 14 pp 1639ndash1662 1998

[37] T A Halgren ldquoCharacterization of MMFF94 MMFF94s andother widely available force fields for conformational energiesand for intermolecular-interaction energies and geometriesrdquoJournal of Computational Chemistry vol 20 1999

[38] C Y Chung H Y Chung W T Sung et al ldquoMoleculardocking for protein folding structure and drug-likenessprediction WSEAS conferencerdquo International Journal ofBiology and Biomedicine vol 1 pp 57ndash63 2005

[39] G Li H Zhou Y Jiang et al ldquoDesign and synthesis of 4-arylpiperidinyl amide and N-arylpiperdin-3-yl-cyclopropanecarboxamide derivatives as novel melatonin receptor ligandsrdquoBioorganic amp Medicinal Chemistry Letters vol 21 no 4pp 1236ndash1242 2011

[40] F J Solis and R J B Wets ldquoMinimization by random searchtechniquesrdquoMathematics of Operations Research vol 6 no 1pp 19ndash30 1981

[41] I A Alswaidan K Sooknah L Rhyman et al ldquo2 4-Ditel-lurouracil and its 5-fluoro derivative )eoretical investiga-tions of structural energetics and ADME parametersrdquoComputational Biology and Chemistry vol 68 pp 56ndash632017

16 Evidence-Based Complementary and Alternative Medicine

[42] M F Fromm ldquoP-glycoprotein a defense mechanism limitingoral bioavailability and CNS accumulation of drugsrdquo Inter-national Journal of Clinical Pharmacology amp Eerapeuticsvol 38 no 2 pp 69ndash74 2000

[43] G Szakacs A Varadi C Ozvegy Laczka and B Sarkadi ldquo)erole of ABC transporters in drug absorption distributionmetabolism excretion and toxicity (ADME-Tox)rdquo Drug Dis-covery Today vol 13 no 9-10 pp 379ndash393 2008

[44] B Testa and S D Kraemer ldquo)e biochemistry of drugmetabolism an introduction part 2 Redox reactions and theirenzymesrdquo ChemInform vol 38 no 23 pp 257ndash405 2007

[45] S Meeran V Baskar S Syed Tajudeen and T K ShabeerldquoDesign ADME profiling and molecular docking simulationof new isoniazid schiff base analogs as MtKasB InhibitorsrdquoAsian Journal of Chemistry and Pharmaceutical Science vol 6pp 20ndash34 2018

[46] J B Baell and G A Holloway ldquoNew substructure filters forremoval of pan assay interference compounds (PAINS) fromscreening libraries and for their exclusion in bioassaysrdquoJournal of Medicinal Chemistry vol 53 no 7 pp 2719ndash27402010

[47] T J Ritchie P Ertl and R Lewis ldquo)e graphical represen-tation of ADME-related molecule properties for medicinalchemistsrdquo Drug Discovery Today vol 16 no 1-2 pp 65ndash722011

[48] Z M Dastjerdi F Namjoyan and M E Azemi ldquoAlphaamylase inhibition activity of some plants extract of Teucriumspeciesrdquo European Journal of Biological Sciences vol 7pp 26ndash31 2015

[49] I M E Lacroix and E C Y Li-Chan ldquoOverview of foodproducts and dietary constituents with antidiabetic propertiesand their putative mechanisms of action a natural approachto complement pharmacotherapy in the management of di-abetesrdquo Molecular Nutrition amp Food Research vol 58 no 1pp 61ndash78 2014

[50] H V Rupasinghe S Sekhon-Loodu T Mantso andM I Panayiotidis ldquoPhytochemicals in regulating fatty acidβ-oxidation Potential underlying mechanisms and their in-volvement in obesity and weight lossrdquo Pharmacology ampEerapeutics vol 165 pp 153ndash163 2016

[51] M Qasim Z Abideen M Y Adnan et al ldquoAntioxidantproperties phenolic composition bioactive compounds andnutritive value of medicinal halophytes commonly used asherbal teasrdquo South African Journal of Botany vol 110pp 240ndash250 2017

[52] B Romano E Pagano V Montanaro A L FortunatoNMilic and F Borrelli ldquoNovel insights into the pharmacologyof flavonoidsrdquo Phytotherapy Research vol 27 pp 1588ndash15962013

[53] A P Rauter A Martins C Borges et al ldquoAntihyperglycaemicand protective effects of flavonoids on streptozotocinndashinduceddiabetic ratsrdquo Phytotherapy Research vol 24 pp S133ndashS1382010

[54] M O Agbo P F Uzor U N Nneji C U OdurukweU B Ogbatue and E C Mbaoji ldquoAntioxidant total phenolicand flavonoid content of selected Nigerian medicinal plantsrdquoDhaka University Journal of Pharmaceutical Science vol 14pp 35ndash41 2015

[55] N Saeed M R Khan and M Shabbir ldquoAntioxidant activitytotal phenolic and total flavonoid contents of whole plantextracts Torilis leptophylla Lrdquo BMC Complementary andAlternative Medicine vol 12 no 1 p 221 2012

[56] M R Kumbhare V Guleha and T Sivakumar ldquoEstimationof total phenolic content cytotoxicity and inndashvitro

antioxidant activity of stem bark of Moringa oleiferardquo AsianPacific Journal of Tropical Disease vol 2 pp 144ndash150 2012

[57] A A Ala B B Olotu and C M D Ohia ldquoAssessment ofcytotoxicity of leaf extracts of andrographis paniculata andaspilia Africana onmurine cellsrdquoArchives of basic and appliedmedicine vol 6 pp 61ndash65 2018

[58] S K Doreddula S R Bonam D P Gaddam B S R DesuN Ramarao and V Pandy ldquoPhytochemical analysis antioxi-dant antistress and nootropic activities of aqueous andmethanolic seed extracts of ladies finger (Abelmoschus escu-lentus L) in micerdquo Ee Scientific World Journal vol 2014Article ID 519848 14 pages 2014

[59] L A Nistor Baldea L C Martineau A Benhaddou-Anda-loussi J T Arnason E Levy and P S Haddad ldquoInhibition ofintestinal glucose absorption by anti-diabetic medicinal plantsderived from the James Bay Cree traditional pharmacopeiardquoJournal of Ethnopharmacology vol 132 no 2 pp 473ndash4822010

[60] N Shehzadi K Hussain N I Bukhari et al ldquoHypoglycemichepatoprotective and molecular docking studies of 5-[(4-chlorophenoxy) methyl]-1 3 4- oxadiazole-2-thiolrdquo Ban-gladesh Journal of Pharmacology vol 13 no 2 pp 149ndash1562018

[61] D Seeliger B L de Groot and V De Pymol ldquoLigand dockingand binding site analysis with PyMOL and AutodockVinardquoJournal of Computer-Aided Molecular Design vol 24pp 417ndash422 2010

[62] W Benalla S Bellahcen and M Bnouham ldquoAntidiabeticmedicinal plants as a source of alpha glucosidase inhibitorsrdquoCurrent Diabetes Reviews vol 6 no 4 pp 247ndash254 2010

[63] R Andleeb M U Ijaz A Rafique et al ldquoBiological activitiesof methanolic extract of aegle marmelos against HN protein ofnewcastle disease virusrdquo Agronomy vol 11 no 9 p 17842021

Evidence-Based Complementary and Alternative Medicine 17

inhibitory activity of methanol plant extract is most likely bypolar compounds that should be investigated further byisolating pure active compounds

At 50ndash200 gml concentrations of T divaricata ex-tract the percentage inhibition increased in a dose-de-pendent manner For the highest and lowestconcentrations respectively the percentage inhibitionranged from 60 to 31 (Table 4) )us by inhibiting thealpha-glucosidase enzyme the extract of T divaricatawhich contains various natural bioactive compoundshelps to reduce the rate of carbohydrate digestionlowering blood glucose levels and maintaining diabeticconditions

Glucose uptake is one of the in vitro methods used toexplore the antihyperglycemic effect of different compounds[60] )e average values of glucose uptake by yeast cells inthis study were 1305plusmn 13 to 695plusmn 478 Shehzadi et al[60] reported the evaluation of antihyperglycemic activitythrough in vitro assays (02 to 263) at 2mgmL which wasbelow the current research values )e results indicated allused concentrations under examination are capable of in-creasing the utilization and uptake of glucose in yeast cells

)e in silico prediction of molecular physicochemicalparameters bioavailability and the pharmacokinetics havebecome more relevant for the investigation of productivepotential drug molecules from a drug discovery standpoint[47] )eoretical experiments play a critical role in presentingaccurate data in a timely and comfortable manner Many freeonline platforms have recently been established for fasterscreening reducing the time and expense of drug testing (noanimal testing) [46] SwissADME is a modern comprehensivemethod developed by the Swiss Institute of Bioinformatics(SIB) that allows drug candidates to have their absorptiondelivery metabolism and excretion (ADME) parametersestimated [45] At the outset of the drug development processADME properties which determine either the potentialdrugrsquos access to the target or its removal by the organism arethe required properties that must be evaluated for the drug tobe selected In silico experiments based on measured phys-icochemical requirements can be used to check these pa-rameters SwissADME also provides information ongastrointestinal absorption (GIA) and blood-brain barrier(BBB) permeability in humans From twenty-six selectedcompounds only eight compounds fulfilled the criteria of

1 6 10-Dodecatriene 7 11-dimethyl-3-methylene

Interactions

Alkyl

2-phenylthiolane Propanamide

Interactions

Alkyl

Pi-Alkyl

Propanamide

Interactions

Conventional Hydrogen Bond

Alkyl

(b)

Figure 3 In silico molecular docking results of interactions between 5kzw proteins with screened compounds as ligand

14 Evidence-Based Complementary and Alternative Medicine

drug-likeness parameters So all of these nine compoundswere further processed for molecular docking by GOLD

To predict the affinity and behavior of small moleculesand drug candidates computational molecular docking iscommonly used to predict the binding orientation to theirprotein targets [61] We used molecular docking to modelvarious bioactive compounds isolated from the Jasmineplant that is known to inhibit glucosidase Because of theirlow price and comparatively greater protection with a lowfrequency of severe gastrointestinal side effects plants orplant-based substances may be a suitable source of gluco-sidase inhibitors [62] Hydrogen bonds play a crucial role inthe structure and interaction of protein-protein or ligand-receptor complexes Hydrogen bonds are important in drugdesign to ensure that the drug is unique to the protein targetTo back up the findings of this research a molecular dockingstudy was performed (cyclopropane tetradecanoic acid 2-octyl- methyl ester 4-(4-methyl-2-biphenylyloxy) phtha-lonitrile) which showed excellent interaction with 5kzwprotein having Gold fitness (3928 3721) and GOLDdocking score of -751 and -653 including the formation ofhydrogen bond with amino acids residues (1610-dodeca-triene 711-dimethyl-3-methylene 2-phenylthiolane andcyclohexane propanoic acid 3-oxo- methyl ester) )esemolecules showed exceptionally good interaction withα-glucosidase protein and can be considered as potentialmolecules that may prove to be beneficial in antiviral activitythrough their direct action on new castle disease [63] )esecompounds showed moderate binding affinity of 32692914 and 2829 and GOLD docking scores of -403 0205and 093 respectively N-methylallylamine propanamidecyclohexene and 3-ethenyl have the least interaction in therange of 2000 1916 and 2383 and docking scores of -016-059 and 014 while 1H-tetrazol-5-amine compoundshowed the least affinity towards 5kzw binding site

5 Conclusion

Since diabetes mellitus is a global epidemic effective drugswith less or no toxicity must be developed and one such wayis the use of herbal medicines having no side effects )isstudy investigated the antidiabetic and antioxidant prop-erties of T divaricata extract and found promising inhibitorsof two carbohydrate-related enzymes T divaricata has richphenolic and flavonoid contents As a flavonoid it has greatantidiabetic potential and also causes active uptake of glu-cose )e methanolic extract of T divaricate has great po-tential for stimulation of α-amylase and α-glucosidase sothat it can be used to treat diabetes In silico docking studiesof phytoactive compounds from T divaricata have beenproven to have potential drug capabilities in terms of theirpharmacokinetic and drug-likeness )e molecular dockinganalysis described some compounds that inhibited thetargets related to diabetes mellitus and showed encouragingresults with prominent inhibitory activity )is study showsthat T divaricata extract which is rich in important bio-active compounds can be used for diabetes It is suggested tocarry out long-term research work to recognize and isolatethe active moieties responsible for antidiabetic property and

to understand the mechanisms involved in glucose-loweringproperties of the plant

Data Availability

Data are available from authors on reasonable demand

Conflicts of Interest

)e authors declare that there are no conflicts of interestregarding the publication of this study

Acknowledgments

)e facilities and support provided by the Department ofZoology Government College University Faisalabad arehighly acknowledged

References

[1] C D Deshmukh and A Jain ldquoDiabetes mellitus a reviewrdquoInternational Journal of Pure and Applied Biosciences vol 3pp 224ndash230 2015

[2] American Diabetes Association (ADA) ldquo5 Lifestyle man-agement Standards of medical care in diabetesmdash2019rdquo Di-abetes Care vol 42 no 1 pp S46ndashS60 2019

[3] A Meeinta C Rojwipaporn R Chanaporn et al ldquoDiabetesmellitus HbA1c and lung function do they are relatedrdquo Di-abetes amp its Complications vol 2 no 3 pp 1ndash6 2018

[4] U Yoon L L Kwok and A Magkidis ldquoEfficacy of lifestyleinterventions in reducing diabetes incidence in patients withimpaired glucose tolerance a systematic review of random-ized controlled trialsrdquo BMC Proceedings vol 6 pp P28ndashP142012

[5] S B Aynalem and A J Zeleke ldquoPrevalence of diabetesmellitus and its risk factors among individuals aged 15 yearsand above in Mizan-Aman town a cross sectional studyrdquoInternational Journal of Endocrinology vol 2018 Article ID9317987 7 pages 2018

[6] D R Whiting L Guariguata C Weil and J Shaw ldquoIDFdiabetes atlas global estimates of the prevalence of diabetesfor 2011 and 2030rdquo Diabetes Research and Clinical Practicevol 94 pp 311ndash321 2011

[7] P Agarwal and R Gupta ldquoAlpha-amylase inhibition can treatdiabetes mellitusrdquo Research Review Journal of Medical HealthScience vol 5 pp 1ndash8 2016

[8] H Kaneto N Katakami M Matsuhisa and T A MatsuokaldquoRole of reactive oxygen species in the progression of type 2diabetes and atherosclerosisrdquo Mediators of Inflammationvol 2010 Article ID 453892 11 pages 2010

[9] Z Sun and R Albert ldquoBoolean models of cellular signalingnetworksrdquo in Handbook of Systems BiologyElsevier Amster-dam Netherlands 2013

[10] M Nazıroglu ldquoNew molecular mechanisms on the activationof TRPM2 channels by oxidative stress and ADP-riboserdquoNeurochemical Research vol 32 pp 1990ndash2001 2007

[11] R Dringen ldquoOxidative and antioxidative potential of brainmicroglial cellsrdquo Antioxidants and Redox Signaling vol 7pp 1223ndash1233 2005

[12] T Zahidi A Lekchiri T Zahidi W Lekchiri and A BerrichialdquoExtraction and comparison of two new peroxidases fromleaves and roots of Brassica oleraceae var ramoserdquo Journal of

Evidence-Based Complementary and Alternative Medicine 15

Materials and Environmental Science vol 9 pp 1398ndash14042018

[13] D M Kasote S S Katyare M V Hegde and H BaeldquoSignificance of antioxidant potential of plants and its rele-vance to therapeutic applicationsrdquo International Journal ofBiological Sciences vol 11 pp 982ndash991 2015

[14] W Kooti M Farokhipour Z Asadzadeh D Ashtary-Larkyand M Asadi-Samani ldquo)e role of medicinal plants in thetreatment of diabetes a systematic reviewrdquo Electronic Phy-sician vol 8 no 1 pp 1832ndash1842 2016

[15] M S Aslam and M S Ahmad ldquoWorldwide importance ofmedicinal plants current and historical perspectivesrdquo RecentAdvances in Biology and Medicine vol 02 p 88 2016

[16] S Ponnusamy R Ravindran S Zinjarde S Bhargava andA R Kumar ldquoEvaluation of traditional Indian antidiabeticmedicinal plants for human pancreatic amylase inhibitoryeffect in vitrordquo Evidence-Based Complementary and Alter-native Medicine vol 2011 Article ID 515647 10 pages 2011

[17] P P Bijeshmon and S George ldquoAntimicrobial activity andpowder microscopy of the flowers of Tabernaemontanadivaricata Rrdquo BRrdquo Indo American Journal of PharmaceuticalResearch vol 4 pp 1601ndash1605 2014

[18] V L Singleton R Orthofer and R M Lamuela-RaventosldquoAnalysis of total phenols and other oxidation substrates andantioxidants by means of folin-ciocalteu reagentrdquoMethods inEnzymology vol 299 pp 152ndash178 1999

[19] J Bao Y Cai M Sun G Wang and H Corke ldquoAnthocy-anins flavonols and free radical scavenging activity of Chi-nese bayberry (Myrica rubra) extracts and their colorproperties and stabilityrdquo Journal of Agricultural and FoodChemistry vol 53 pp 2327ndash2332 2005

[20] M Mohebbi-Fani A Mirzaei S Nazifi and M R TabandehldquoOxidative status and antioxidant enzyme activities inerythrocytes from breeding and pregnant ewes grazing nat-ural pastures in dry seasonrdquo Revue de Medecine Veterinairevol 163 pp 454ndash460 2012

[21] G H Onsa N bin Saari J Selamat and J Bakar ldquoPurificationand characterization of membrane-bound peroxidases fromMetroxylon sagurdquo Food Chemistry vol 85 no 3 pp 365ndash3762004

[22] M Kumar A J Bijo R S Baghel C Reddy and B JhaldquoSelenium and spermine alleviate cadmium induced toxicityin the red seaweed Gracilaria dura by regulating antioxidantsand DNA methylationrdquo Plant Physiology and Biochemistryvol 51 pp 129ndash138 2012

[23] W A Powell C M Catranis and C A Maynard ldquoDesign ofself-processing antimicrobial peptides for plant protectionrdquoLetters in Applied Microbiology vol 31 pp 163ndash168 2000

[24] L J Shai P Masoko M P Mokgotho et al ldquoYeast alphaglucosidase inhibitory and antioxidant activities of six me-dicinal plants collected in Phalaborwa South Africardquo SouthAfrican Journal of Botany vol 76 pp 465ndash470 2010

[25] A O Ademiluyi and G Oboh ldquoSoybean phenolic-rich extractsinhibit key-enzymes linked to type 2 diabetes (α-amylase andα-glucosidase) and hypertension (angiotensin I convertingenzyme) in vitrordquo Experimental amp Toxicologic Pathologyvol 65 pp 305ndash309 2013

[26] V P Cirillo ldquoMechanism of glucose transport across the yeastcell membranerdquo Journal of Bacteriology vol 84 pp 485ndash4911962

[27] C Kalaimagal ldquoIdentification of bioactive compounds inflower of Tabernaemontana divaricata (l) using gas chro-matographyndashmass spectrometry analysisrdquo Asian Journal of

Pharmaceutical and Clinical Research vol 12 pp 129ndash1322019

[28] H H Rassem A Hamid Nour and R Mohamed YunusldquoAnalysis of bioactive compounds for Jasmine flower via Gaschromatography-mass spectrometry (GC-MS)rdquo MalaysianJournal of Fundamental and Applied Sciences vol 14 no 2pp 198ndash201 2018

[29] M S Ali Khan AMMat Jais and A Afreen ldquoAnalogous andantioxidant activity mediated gastroprotective action ofTabernaemontana divaricata (L) R Br flower methanolicextract against chemically induced gastric ulcers in ratsrdquoBioMed Research International vol 2013 Article ID 18547618 pages 2013

[30] D F Veber S R Johnson H Y Cheng B R SmithK W Ward and K D Kopple ldquoMolecular properties thatinfluence the oral bioavailability of drug candidatesrdquo Journalof Medicinal Chemistry vol 45 no 12 pp 2615ndash2623 2002

[31] C A Lipinski A Lombardo B W Dominy F Dominy andP J Feeney ldquoExperimental and computational approaches toestimate solubility and permeability in drug discovery anddevelopment settingsrdquo Advanced Drug Delivery Reviewsvol 46 pp 3ndash26 2001

[32] A K Ghose V N Viswanadhan and J J Wendoloski ldquoAknowledge-based approach in designing combinatorial ormedicinal chemistry libraries for drug discovery 1 A qualitativeand quantitative characterization of known drug databasesrdquoJournal of Combinatorial Chemistry vol 1 pp 55ndash68 1999

[33] Z Bikadi and E Hazai ldquoApplication of the PM6 semi-em-pirical method to modeling proteins enhances docking ac-curacy of AutoDockrdquo Journal of Cheminformatics vol 1p 15 2009

[34] S S Azam A Saroosh N Zaman and S Raza ldquoRole ofN-acetylserotonin O-methyltransferase in bipolar disordersand its dynamicsrdquo Journal of Molecular Liquids vol 182pp 25ndash31 2013

[35] O Trott and A J Olson ldquoAutoDockVina improving thespeed and accuracy of docking with a new scoring functionefficient optimization and multi-threadingrdquo Journal ofComputational Chemistry vol 31 pp 455ndash461 2010

[36] G M Morris D S Goodsell R S Halliday et al ldquoAutomateddocking using a Lamarckian genetic algorithm and an em-pirical binding free energy functionrdquo Journal of Computa-tional Chemistry vol 19 no 14 pp 1639ndash1662 1998

[37] T A Halgren ldquoCharacterization of MMFF94 MMFF94s andother widely available force fields for conformational energiesand for intermolecular-interaction energies and geometriesrdquoJournal of Computational Chemistry vol 20 1999

[38] C Y Chung H Y Chung W T Sung et al ldquoMoleculardocking for protein folding structure and drug-likenessprediction WSEAS conferencerdquo International Journal ofBiology and Biomedicine vol 1 pp 57ndash63 2005

[39] G Li H Zhou Y Jiang et al ldquoDesign and synthesis of 4-arylpiperidinyl amide and N-arylpiperdin-3-yl-cyclopropanecarboxamide derivatives as novel melatonin receptor ligandsrdquoBioorganic amp Medicinal Chemistry Letters vol 21 no 4pp 1236ndash1242 2011

[40] F J Solis and R J B Wets ldquoMinimization by random searchtechniquesrdquoMathematics of Operations Research vol 6 no 1pp 19ndash30 1981

[41] I A Alswaidan K Sooknah L Rhyman et al ldquo2 4-Ditel-lurouracil and its 5-fluoro derivative )eoretical investiga-tions of structural energetics and ADME parametersrdquoComputational Biology and Chemistry vol 68 pp 56ndash632017

16 Evidence-Based Complementary and Alternative Medicine

[42] M F Fromm ldquoP-glycoprotein a defense mechanism limitingoral bioavailability and CNS accumulation of drugsrdquo Inter-national Journal of Clinical Pharmacology amp Eerapeuticsvol 38 no 2 pp 69ndash74 2000

[43] G Szakacs A Varadi C Ozvegy Laczka and B Sarkadi ldquo)erole of ABC transporters in drug absorption distributionmetabolism excretion and toxicity (ADME-Tox)rdquo Drug Dis-covery Today vol 13 no 9-10 pp 379ndash393 2008

[44] B Testa and S D Kraemer ldquo)e biochemistry of drugmetabolism an introduction part 2 Redox reactions and theirenzymesrdquo ChemInform vol 38 no 23 pp 257ndash405 2007

[45] S Meeran V Baskar S Syed Tajudeen and T K ShabeerldquoDesign ADME profiling and molecular docking simulationof new isoniazid schiff base analogs as MtKasB InhibitorsrdquoAsian Journal of Chemistry and Pharmaceutical Science vol 6pp 20ndash34 2018

[46] J B Baell and G A Holloway ldquoNew substructure filters forremoval of pan assay interference compounds (PAINS) fromscreening libraries and for their exclusion in bioassaysrdquoJournal of Medicinal Chemistry vol 53 no 7 pp 2719ndash27402010

[47] T J Ritchie P Ertl and R Lewis ldquo)e graphical represen-tation of ADME-related molecule properties for medicinalchemistsrdquo Drug Discovery Today vol 16 no 1-2 pp 65ndash722011

[48] Z M Dastjerdi F Namjoyan and M E Azemi ldquoAlphaamylase inhibition activity of some plants extract of Teucriumspeciesrdquo European Journal of Biological Sciences vol 7pp 26ndash31 2015

[49] I M E Lacroix and E C Y Li-Chan ldquoOverview of foodproducts and dietary constituents with antidiabetic propertiesand their putative mechanisms of action a natural approachto complement pharmacotherapy in the management of di-abetesrdquo Molecular Nutrition amp Food Research vol 58 no 1pp 61ndash78 2014

[50] H V Rupasinghe S Sekhon-Loodu T Mantso andM I Panayiotidis ldquoPhytochemicals in regulating fatty acidβ-oxidation Potential underlying mechanisms and their in-volvement in obesity and weight lossrdquo Pharmacology ampEerapeutics vol 165 pp 153ndash163 2016

[51] M Qasim Z Abideen M Y Adnan et al ldquoAntioxidantproperties phenolic composition bioactive compounds andnutritive value of medicinal halophytes commonly used asherbal teasrdquo South African Journal of Botany vol 110pp 240ndash250 2017

[52] B Romano E Pagano V Montanaro A L FortunatoNMilic and F Borrelli ldquoNovel insights into the pharmacologyof flavonoidsrdquo Phytotherapy Research vol 27 pp 1588ndash15962013

[53] A P Rauter A Martins C Borges et al ldquoAntihyperglycaemicand protective effects of flavonoids on streptozotocinndashinduceddiabetic ratsrdquo Phytotherapy Research vol 24 pp S133ndashS1382010

[54] M O Agbo P F Uzor U N Nneji C U OdurukweU B Ogbatue and E C Mbaoji ldquoAntioxidant total phenolicand flavonoid content of selected Nigerian medicinal plantsrdquoDhaka University Journal of Pharmaceutical Science vol 14pp 35ndash41 2015

[55] N Saeed M R Khan and M Shabbir ldquoAntioxidant activitytotal phenolic and total flavonoid contents of whole plantextracts Torilis leptophylla Lrdquo BMC Complementary andAlternative Medicine vol 12 no 1 p 221 2012

[56] M R Kumbhare V Guleha and T Sivakumar ldquoEstimationof total phenolic content cytotoxicity and inndashvitro

antioxidant activity of stem bark of Moringa oleiferardquo AsianPacific Journal of Tropical Disease vol 2 pp 144ndash150 2012

[57] A A Ala B B Olotu and C M D Ohia ldquoAssessment ofcytotoxicity of leaf extracts of andrographis paniculata andaspilia Africana onmurine cellsrdquoArchives of basic and appliedmedicine vol 6 pp 61ndash65 2018

[58] S K Doreddula S R Bonam D P Gaddam B S R DesuN Ramarao and V Pandy ldquoPhytochemical analysis antioxi-dant antistress and nootropic activities of aqueous andmethanolic seed extracts of ladies finger (Abelmoschus escu-lentus L) in micerdquo Ee Scientific World Journal vol 2014Article ID 519848 14 pages 2014

[59] L A Nistor Baldea L C Martineau A Benhaddou-Anda-loussi J T Arnason E Levy and P S Haddad ldquoInhibition ofintestinal glucose absorption by anti-diabetic medicinal plantsderived from the James Bay Cree traditional pharmacopeiardquoJournal of Ethnopharmacology vol 132 no 2 pp 473ndash4822010

[60] N Shehzadi K Hussain N I Bukhari et al ldquoHypoglycemichepatoprotective and molecular docking studies of 5-[(4-chlorophenoxy) methyl]-1 3 4- oxadiazole-2-thiolrdquo Ban-gladesh Journal of Pharmacology vol 13 no 2 pp 149ndash1562018

[61] D Seeliger B L de Groot and V De Pymol ldquoLigand dockingand binding site analysis with PyMOL and AutodockVinardquoJournal of Computer-Aided Molecular Design vol 24pp 417ndash422 2010

[62] W Benalla S Bellahcen and M Bnouham ldquoAntidiabeticmedicinal plants as a source of alpha glucosidase inhibitorsrdquoCurrent Diabetes Reviews vol 6 no 4 pp 247ndash254 2010

[63] R Andleeb M U Ijaz A Rafique et al ldquoBiological activitiesof methanolic extract of aegle marmelos against HN protein ofnewcastle disease virusrdquo Agronomy vol 11 no 9 p 17842021

Evidence-Based Complementary and Alternative Medicine 17

drug-likeness parameters So all of these nine compoundswere further processed for molecular docking by GOLD

To predict the affinity and behavior of small moleculesand drug candidates computational molecular docking iscommonly used to predict the binding orientation to theirprotein targets [61] We used molecular docking to modelvarious bioactive compounds isolated from the Jasmineplant that is known to inhibit glucosidase Because of theirlow price and comparatively greater protection with a lowfrequency of severe gastrointestinal side effects plants orplant-based substances may be a suitable source of gluco-sidase inhibitors [62] Hydrogen bonds play a crucial role inthe structure and interaction of protein-protein or ligand-receptor complexes Hydrogen bonds are important in drugdesign to ensure that the drug is unique to the protein targetTo back up the findings of this research a molecular dockingstudy was performed (cyclopropane tetradecanoic acid 2-octyl- methyl ester 4-(4-methyl-2-biphenylyloxy) phtha-lonitrile) which showed excellent interaction with 5kzwprotein having Gold fitness (3928 3721) and GOLDdocking score of -751 and -653 including the formation ofhydrogen bond with amino acids residues (1610-dodeca-triene 711-dimethyl-3-methylene 2-phenylthiolane andcyclohexane propanoic acid 3-oxo- methyl ester) )esemolecules showed exceptionally good interaction withα-glucosidase protein and can be considered as potentialmolecules that may prove to be beneficial in antiviral activitythrough their direct action on new castle disease [63] )esecompounds showed moderate binding affinity of 32692914 and 2829 and GOLD docking scores of -403 0205and 093 respectively N-methylallylamine propanamidecyclohexene and 3-ethenyl have the least interaction in therange of 2000 1916 and 2383 and docking scores of -016-059 and 014 while 1H-tetrazol-5-amine compoundshowed the least affinity towards 5kzw binding site

5 Conclusion

Since diabetes mellitus is a global epidemic effective drugswith less or no toxicity must be developed and one such wayis the use of herbal medicines having no side effects )isstudy investigated the antidiabetic and antioxidant prop-erties of T divaricata extract and found promising inhibitorsof two carbohydrate-related enzymes T divaricata has richphenolic and flavonoid contents As a flavonoid it has greatantidiabetic potential and also causes active uptake of glu-cose )e methanolic extract of T divaricate has great po-tential for stimulation of α-amylase and α-glucosidase sothat it can be used to treat diabetes In silico docking studiesof phytoactive compounds from T divaricata have beenproven to have potential drug capabilities in terms of theirpharmacokinetic and drug-likeness )e molecular dockinganalysis described some compounds that inhibited thetargets related to diabetes mellitus and showed encouragingresults with prominent inhibitory activity )is study showsthat T divaricata extract which is rich in important bio-active compounds can be used for diabetes It is suggested tocarry out long-term research work to recognize and isolatethe active moieties responsible for antidiabetic property and

to understand the mechanisms involved in glucose-loweringproperties of the plant

Data Availability

Data are available from authors on reasonable demand

Conflicts of Interest

)e authors declare that there are no conflicts of interestregarding the publication of this study

Acknowledgments

)e facilities and support provided by the Department ofZoology Government College University Faisalabad arehighly acknowledged

References

[1] C D Deshmukh and A Jain ldquoDiabetes mellitus a reviewrdquoInternational Journal of Pure and Applied Biosciences vol 3pp 224ndash230 2015

[2] American Diabetes Association (ADA) ldquo5 Lifestyle man-agement Standards of medical care in diabetesmdash2019rdquo Di-abetes Care vol 42 no 1 pp S46ndashS60 2019

[3] A Meeinta C Rojwipaporn R Chanaporn et al ldquoDiabetesmellitus HbA1c and lung function do they are relatedrdquo Di-abetes amp its Complications vol 2 no 3 pp 1ndash6 2018

[4] U Yoon L L Kwok and A Magkidis ldquoEfficacy of lifestyleinterventions in reducing diabetes incidence in patients withimpaired glucose tolerance a systematic review of random-ized controlled trialsrdquo BMC Proceedings vol 6 pp P28ndashP142012

[5] S B Aynalem and A J Zeleke ldquoPrevalence of diabetesmellitus and its risk factors among individuals aged 15 yearsand above in Mizan-Aman town a cross sectional studyrdquoInternational Journal of Endocrinology vol 2018 Article ID9317987 7 pages 2018

[6] D R Whiting L Guariguata C Weil and J Shaw ldquoIDFdiabetes atlas global estimates of the prevalence of diabetesfor 2011 and 2030rdquo Diabetes Research and Clinical Practicevol 94 pp 311ndash321 2011

[7] P Agarwal and R Gupta ldquoAlpha-amylase inhibition can treatdiabetes mellitusrdquo Research Review Journal of Medical HealthScience vol 5 pp 1ndash8 2016

[8] H Kaneto N Katakami M Matsuhisa and T A MatsuokaldquoRole of reactive oxygen species in the progression of type 2diabetes and atherosclerosisrdquo Mediators of Inflammationvol 2010 Article ID 453892 11 pages 2010

[9] Z Sun and R Albert ldquoBoolean models of cellular signalingnetworksrdquo in Handbook of Systems BiologyElsevier Amster-dam Netherlands 2013

[10] M Nazıroglu ldquoNew molecular mechanisms on the activationof TRPM2 channels by oxidative stress and ADP-riboserdquoNeurochemical Research vol 32 pp 1990ndash2001 2007

[11] R Dringen ldquoOxidative and antioxidative potential of brainmicroglial cellsrdquo Antioxidants and Redox Signaling vol 7pp 1223ndash1233 2005

[12] T Zahidi A Lekchiri T Zahidi W Lekchiri and A BerrichialdquoExtraction and comparison of two new peroxidases fromleaves and roots of Brassica oleraceae var ramoserdquo Journal of

Evidence-Based Complementary and Alternative Medicine 15

Materials and Environmental Science vol 9 pp 1398ndash14042018

[13] D M Kasote S S Katyare M V Hegde and H BaeldquoSignificance of antioxidant potential of plants and its rele-vance to therapeutic applicationsrdquo International Journal ofBiological Sciences vol 11 pp 982ndash991 2015

[14] W Kooti M Farokhipour Z Asadzadeh D Ashtary-Larkyand M Asadi-Samani ldquo)e role of medicinal plants in thetreatment of diabetes a systematic reviewrdquo Electronic Phy-sician vol 8 no 1 pp 1832ndash1842 2016

[15] M S Aslam and M S Ahmad ldquoWorldwide importance ofmedicinal plants current and historical perspectivesrdquo RecentAdvances in Biology and Medicine vol 02 p 88 2016

[16] S Ponnusamy R Ravindran S Zinjarde S Bhargava andA R Kumar ldquoEvaluation of traditional Indian antidiabeticmedicinal plants for human pancreatic amylase inhibitoryeffect in vitrordquo Evidence-Based Complementary and Alter-native Medicine vol 2011 Article ID 515647 10 pages 2011

[17] P P Bijeshmon and S George ldquoAntimicrobial activity andpowder microscopy of the flowers of Tabernaemontanadivaricata Rrdquo BRrdquo Indo American Journal of PharmaceuticalResearch vol 4 pp 1601ndash1605 2014

[18] V L Singleton R Orthofer and R M Lamuela-RaventosldquoAnalysis of total phenols and other oxidation substrates andantioxidants by means of folin-ciocalteu reagentrdquoMethods inEnzymology vol 299 pp 152ndash178 1999

[19] J Bao Y Cai M Sun G Wang and H Corke ldquoAnthocy-anins flavonols and free radical scavenging activity of Chi-nese bayberry (Myrica rubra) extracts and their colorproperties and stabilityrdquo Journal of Agricultural and FoodChemistry vol 53 pp 2327ndash2332 2005

[20] M Mohebbi-Fani A Mirzaei S Nazifi and M R TabandehldquoOxidative status and antioxidant enzyme activities inerythrocytes from breeding and pregnant ewes grazing nat-ural pastures in dry seasonrdquo Revue de Medecine Veterinairevol 163 pp 454ndash460 2012

[21] G H Onsa N bin Saari J Selamat and J Bakar ldquoPurificationand characterization of membrane-bound peroxidases fromMetroxylon sagurdquo Food Chemistry vol 85 no 3 pp 365ndash3762004

[22] M Kumar A J Bijo R S Baghel C Reddy and B JhaldquoSelenium and spermine alleviate cadmium induced toxicityin the red seaweed Gracilaria dura by regulating antioxidantsand DNA methylationrdquo Plant Physiology and Biochemistryvol 51 pp 129ndash138 2012

[23] W A Powell C M Catranis and C A Maynard ldquoDesign ofself-processing antimicrobial peptides for plant protectionrdquoLetters in Applied Microbiology vol 31 pp 163ndash168 2000

[24] L J Shai P Masoko M P Mokgotho et al ldquoYeast alphaglucosidase inhibitory and antioxidant activities of six me-dicinal plants collected in Phalaborwa South Africardquo SouthAfrican Journal of Botany vol 76 pp 465ndash470 2010

[25] A O Ademiluyi and G Oboh ldquoSoybean phenolic-rich extractsinhibit key-enzymes linked to type 2 diabetes (α-amylase andα-glucosidase) and hypertension (angiotensin I convertingenzyme) in vitrordquo Experimental amp Toxicologic Pathologyvol 65 pp 305ndash309 2013

[26] V P Cirillo ldquoMechanism of glucose transport across the yeastcell membranerdquo Journal of Bacteriology vol 84 pp 485ndash4911962

[27] C Kalaimagal ldquoIdentification of bioactive compounds inflower of Tabernaemontana divaricata (l) using gas chro-matographyndashmass spectrometry analysisrdquo Asian Journal of

Pharmaceutical and Clinical Research vol 12 pp 129ndash1322019

[28] H H Rassem A Hamid Nour and R Mohamed YunusldquoAnalysis of bioactive compounds for Jasmine flower via Gaschromatography-mass spectrometry (GC-MS)rdquo MalaysianJournal of Fundamental and Applied Sciences vol 14 no 2pp 198ndash201 2018

[29] M S Ali Khan AMMat Jais and A Afreen ldquoAnalogous andantioxidant activity mediated gastroprotective action ofTabernaemontana divaricata (L) R Br flower methanolicextract against chemically induced gastric ulcers in ratsrdquoBioMed Research International vol 2013 Article ID 18547618 pages 2013

[30] D F Veber S R Johnson H Y Cheng B R SmithK W Ward and K D Kopple ldquoMolecular properties thatinfluence the oral bioavailability of drug candidatesrdquo Journalof Medicinal Chemistry vol 45 no 12 pp 2615ndash2623 2002

[31] C A Lipinski A Lombardo B W Dominy F Dominy andP J Feeney ldquoExperimental and computational approaches toestimate solubility and permeability in drug discovery anddevelopment settingsrdquo Advanced Drug Delivery Reviewsvol 46 pp 3ndash26 2001

[32] A K Ghose V N Viswanadhan and J J Wendoloski ldquoAknowledge-based approach in designing combinatorial ormedicinal chemistry libraries for drug discovery 1 A qualitativeand quantitative characterization of known drug databasesrdquoJournal of Combinatorial Chemistry vol 1 pp 55ndash68 1999

[33] Z Bikadi and E Hazai ldquoApplication of the PM6 semi-em-pirical method to modeling proteins enhances docking ac-curacy of AutoDockrdquo Journal of Cheminformatics vol 1p 15 2009

[34] S S Azam A Saroosh N Zaman and S Raza ldquoRole ofN-acetylserotonin O-methyltransferase in bipolar disordersand its dynamicsrdquo Journal of Molecular Liquids vol 182pp 25ndash31 2013

[35] O Trott and A J Olson ldquoAutoDockVina improving thespeed and accuracy of docking with a new scoring functionefficient optimization and multi-threadingrdquo Journal ofComputational Chemistry vol 31 pp 455ndash461 2010

[36] G M Morris D S Goodsell R S Halliday et al ldquoAutomateddocking using a Lamarckian genetic algorithm and an em-pirical binding free energy functionrdquo Journal of Computa-tional Chemistry vol 19 no 14 pp 1639ndash1662 1998

[37] T A Halgren ldquoCharacterization of MMFF94 MMFF94s andother widely available force fields for conformational energiesand for intermolecular-interaction energies and geometriesrdquoJournal of Computational Chemistry vol 20 1999

[38] C Y Chung H Y Chung W T Sung et al ldquoMoleculardocking for protein folding structure and drug-likenessprediction WSEAS conferencerdquo International Journal ofBiology and Biomedicine vol 1 pp 57ndash63 2005

[39] G Li H Zhou Y Jiang et al ldquoDesign and synthesis of 4-arylpiperidinyl amide and N-arylpiperdin-3-yl-cyclopropanecarboxamide derivatives as novel melatonin receptor ligandsrdquoBioorganic amp Medicinal Chemistry Letters vol 21 no 4pp 1236ndash1242 2011

[40] F J Solis and R J B Wets ldquoMinimization by random searchtechniquesrdquoMathematics of Operations Research vol 6 no 1pp 19ndash30 1981

[41] I A Alswaidan K Sooknah L Rhyman et al ldquo2 4-Ditel-lurouracil and its 5-fluoro derivative )eoretical investiga-tions of structural energetics and ADME parametersrdquoComputational Biology and Chemistry vol 68 pp 56ndash632017

16 Evidence-Based Complementary and Alternative Medicine

[42] M F Fromm ldquoP-glycoprotein a defense mechanism limitingoral bioavailability and CNS accumulation of drugsrdquo Inter-national Journal of Clinical Pharmacology amp Eerapeuticsvol 38 no 2 pp 69ndash74 2000

[43] G Szakacs A Varadi C Ozvegy Laczka and B Sarkadi ldquo)erole of ABC transporters in drug absorption distributionmetabolism excretion and toxicity (ADME-Tox)rdquo Drug Dis-covery Today vol 13 no 9-10 pp 379ndash393 2008

[44] B Testa and S D Kraemer ldquo)e biochemistry of drugmetabolism an introduction part 2 Redox reactions and theirenzymesrdquo ChemInform vol 38 no 23 pp 257ndash405 2007

[45] S Meeran V Baskar S Syed Tajudeen and T K ShabeerldquoDesign ADME profiling and molecular docking simulationof new isoniazid schiff base analogs as MtKasB InhibitorsrdquoAsian Journal of Chemistry and Pharmaceutical Science vol 6pp 20ndash34 2018

[46] J B Baell and G A Holloway ldquoNew substructure filters forremoval of pan assay interference compounds (PAINS) fromscreening libraries and for their exclusion in bioassaysrdquoJournal of Medicinal Chemistry vol 53 no 7 pp 2719ndash27402010

[47] T J Ritchie P Ertl and R Lewis ldquo)e graphical represen-tation of ADME-related molecule properties for medicinalchemistsrdquo Drug Discovery Today vol 16 no 1-2 pp 65ndash722011

[48] Z M Dastjerdi F Namjoyan and M E Azemi ldquoAlphaamylase inhibition activity of some plants extract of Teucriumspeciesrdquo European Journal of Biological Sciences vol 7pp 26ndash31 2015

[49] I M E Lacroix and E C Y Li-Chan ldquoOverview of foodproducts and dietary constituents with antidiabetic propertiesand their putative mechanisms of action a natural approachto complement pharmacotherapy in the management of di-abetesrdquo Molecular Nutrition amp Food Research vol 58 no 1pp 61ndash78 2014

[50] H V Rupasinghe S Sekhon-Loodu T Mantso andM I Panayiotidis ldquoPhytochemicals in regulating fatty acidβ-oxidation Potential underlying mechanisms and their in-volvement in obesity and weight lossrdquo Pharmacology ampEerapeutics vol 165 pp 153ndash163 2016

[51] M Qasim Z Abideen M Y Adnan et al ldquoAntioxidantproperties phenolic composition bioactive compounds andnutritive value of medicinal halophytes commonly used asherbal teasrdquo South African Journal of Botany vol 110pp 240ndash250 2017

[52] B Romano E Pagano V Montanaro A L FortunatoNMilic and F Borrelli ldquoNovel insights into the pharmacologyof flavonoidsrdquo Phytotherapy Research vol 27 pp 1588ndash15962013

[53] A P Rauter A Martins C Borges et al ldquoAntihyperglycaemicand protective effects of flavonoids on streptozotocinndashinduceddiabetic ratsrdquo Phytotherapy Research vol 24 pp S133ndashS1382010

[54] M O Agbo P F Uzor U N Nneji C U OdurukweU B Ogbatue and E C Mbaoji ldquoAntioxidant total phenolicand flavonoid content of selected Nigerian medicinal plantsrdquoDhaka University Journal of Pharmaceutical Science vol 14pp 35ndash41 2015

[55] N Saeed M R Khan and M Shabbir ldquoAntioxidant activitytotal phenolic and total flavonoid contents of whole plantextracts Torilis leptophylla Lrdquo BMC Complementary andAlternative Medicine vol 12 no 1 p 221 2012

[56] M R Kumbhare V Guleha and T Sivakumar ldquoEstimationof total phenolic content cytotoxicity and inndashvitro

antioxidant activity of stem bark of Moringa oleiferardquo AsianPacific Journal of Tropical Disease vol 2 pp 144ndash150 2012

[57] A A Ala B B Olotu and C M D Ohia ldquoAssessment ofcytotoxicity of leaf extracts of andrographis paniculata andaspilia Africana onmurine cellsrdquoArchives of basic and appliedmedicine vol 6 pp 61ndash65 2018

[58] S K Doreddula S R Bonam D P Gaddam B S R DesuN Ramarao and V Pandy ldquoPhytochemical analysis antioxi-dant antistress and nootropic activities of aqueous andmethanolic seed extracts of ladies finger (Abelmoschus escu-lentus L) in micerdquo Ee Scientific World Journal vol 2014Article ID 519848 14 pages 2014

[59] L A Nistor Baldea L C Martineau A Benhaddou-Anda-loussi J T Arnason E Levy and P S Haddad ldquoInhibition ofintestinal glucose absorption by anti-diabetic medicinal plantsderived from the James Bay Cree traditional pharmacopeiardquoJournal of Ethnopharmacology vol 132 no 2 pp 473ndash4822010

[60] N Shehzadi K Hussain N I Bukhari et al ldquoHypoglycemichepatoprotective and molecular docking studies of 5-[(4-chlorophenoxy) methyl]-1 3 4- oxadiazole-2-thiolrdquo Ban-gladesh Journal of Pharmacology vol 13 no 2 pp 149ndash1562018

[61] D Seeliger B L de Groot and V De Pymol ldquoLigand dockingand binding site analysis with PyMOL and AutodockVinardquoJournal of Computer-Aided Molecular Design vol 24pp 417ndash422 2010

[62] W Benalla S Bellahcen and M Bnouham ldquoAntidiabeticmedicinal plants as a source of alpha glucosidase inhibitorsrdquoCurrent Diabetes Reviews vol 6 no 4 pp 247ndash254 2010

[63] R Andleeb M U Ijaz A Rafique et al ldquoBiological activitiesof methanolic extract of aegle marmelos against HN protein ofnewcastle disease virusrdquo Agronomy vol 11 no 9 p 17842021

Evidence-Based Complementary and Alternative Medicine 17

Materials and Environmental Science vol 9 pp 1398ndash14042018

[13] D M Kasote S S Katyare M V Hegde and H BaeldquoSignificance of antioxidant potential of plants and its rele-vance to therapeutic applicationsrdquo International Journal ofBiological Sciences vol 11 pp 982ndash991 2015

[14] W Kooti M Farokhipour Z Asadzadeh D Ashtary-Larkyand M Asadi-Samani ldquo)e role of medicinal plants in thetreatment of diabetes a systematic reviewrdquo Electronic Phy-sician vol 8 no 1 pp 1832ndash1842 2016

[15] M S Aslam and M S Ahmad ldquoWorldwide importance ofmedicinal plants current and historical perspectivesrdquo RecentAdvances in Biology and Medicine vol 02 p 88 2016

[16] S Ponnusamy R Ravindran S Zinjarde S Bhargava andA R Kumar ldquoEvaluation of traditional Indian antidiabeticmedicinal plants for human pancreatic amylase inhibitoryeffect in vitrordquo Evidence-Based Complementary and Alter-native Medicine vol 2011 Article ID 515647 10 pages 2011

[17] P P Bijeshmon and S George ldquoAntimicrobial activity andpowder microscopy of the flowers of Tabernaemontanadivaricata Rrdquo BRrdquo Indo American Journal of PharmaceuticalResearch vol 4 pp 1601ndash1605 2014

[18] V L Singleton R Orthofer and R M Lamuela-RaventosldquoAnalysis of total phenols and other oxidation substrates andantioxidants by means of folin-ciocalteu reagentrdquoMethods inEnzymology vol 299 pp 152ndash178 1999

[19] J Bao Y Cai M Sun G Wang and H Corke ldquoAnthocy-anins flavonols and free radical scavenging activity of Chi-nese bayberry (Myrica rubra) extracts and their colorproperties and stabilityrdquo Journal of Agricultural and FoodChemistry vol 53 pp 2327ndash2332 2005

[20] M Mohebbi-Fani A Mirzaei S Nazifi and M R TabandehldquoOxidative status and antioxidant enzyme activities inerythrocytes from breeding and pregnant ewes grazing nat-ural pastures in dry seasonrdquo Revue de Medecine Veterinairevol 163 pp 454ndash460 2012

[21] G H Onsa N bin Saari J Selamat and J Bakar ldquoPurificationand characterization of membrane-bound peroxidases fromMetroxylon sagurdquo Food Chemistry vol 85 no 3 pp 365ndash3762004

[22] M Kumar A J Bijo R S Baghel C Reddy and B JhaldquoSelenium and spermine alleviate cadmium induced toxicityin the red seaweed Gracilaria dura by regulating antioxidantsand DNA methylationrdquo Plant Physiology and Biochemistryvol 51 pp 129ndash138 2012

[23] W A Powell C M Catranis and C A Maynard ldquoDesign ofself-processing antimicrobial peptides for plant protectionrdquoLetters in Applied Microbiology vol 31 pp 163ndash168 2000

[24] L J Shai P Masoko M P Mokgotho et al ldquoYeast alphaglucosidase inhibitory and antioxidant activities of six me-dicinal plants collected in Phalaborwa South Africardquo SouthAfrican Journal of Botany vol 76 pp 465ndash470 2010

[25] A O Ademiluyi and G Oboh ldquoSoybean phenolic-rich extractsinhibit key-enzymes linked to type 2 diabetes (α-amylase andα-glucosidase) and hypertension (angiotensin I convertingenzyme) in vitrordquo Experimental amp Toxicologic Pathologyvol 65 pp 305ndash309 2013

[26] V P Cirillo ldquoMechanism of glucose transport across the yeastcell membranerdquo Journal of Bacteriology vol 84 pp 485ndash4911962

[27] C Kalaimagal ldquoIdentification of bioactive compounds inflower of Tabernaemontana divaricata (l) using gas chro-matographyndashmass spectrometry analysisrdquo Asian Journal of

Pharmaceutical and Clinical Research vol 12 pp 129ndash1322019

[28] H H Rassem A Hamid Nour and R Mohamed YunusldquoAnalysis of bioactive compounds for Jasmine flower via Gaschromatography-mass spectrometry (GC-MS)rdquo MalaysianJournal of Fundamental and Applied Sciences vol 14 no 2pp 198ndash201 2018

[29] M S Ali Khan AMMat Jais and A Afreen ldquoAnalogous andantioxidant activity mediated gastroprotective action ofTabernaemontana divaricata (L) R Br flower methanolicextract against chemically induced gastric ulcers in ratsrdquoBioMed Research International vol 2013 Article ID 18547618 pages 2013

[30] D F Veber S R Johnson H Y Cheng B R SmithK W Ward and K D Kopple ldquoMolecular properties thatinfluence the oral bioavailability of drug candidatesrdquo Journalof Medicinal Chemistry vol 45 no 12 pp 2615ndash2623 2002

[31] C A Lipinski A Lombardo B W Dominy F Dominy andP J Feeney ldquoExperimental and computational approaches toestimate solubility and permeability in drug discovery anddevelopment settingsrdquo Advanced Drug Delivery Reviewsvol 46 pp 3ndash26 2001

[32] A K Ghose V N Viswanadhan and J J Wendoloski ldquoAknowledge-based approach in designing combinatorial ormedicinal chemistry libraries for drug discovery 1 A qualitativeand quantitative characterization of known drug databasesrdquoJournal of Combinatorial Chemistry vol 1 pp 55ndash68 1999

[33] Z Bikadi and E Hazai ldquoApplication of the PM6 semi-em-pirical method to modeling proteins enhances docking ac-curacy of AutoDockrdquo Journal of Cheminformatics vol 1p 15 2009

[34] S S Azam A Saroosh N Zaman and S Raza ldquoRole ofN-acetylserotonin O-methyltransferase in bipolar disordersand its dynamicsrdquo Journal of Molecular Liquids vol 182pp 25ndash31 2013

[35] O Trott and A J Olson ldquoAutoDockVina improving thespeed and accuracy of docking with a new scoring functionefficient optimization and multi-threadingrdquo Journal ofComputational Chemistry vol 31 pp 455ndash461 2010

[36] G M Morris D S Goodsell R S Halliday et al ldquoAutomateddocking using a Lamarckian genetic algorithm and an em-pirical binding free energy functionrdquo Journal of Computa-tional Chemistry vol 19 no 14 pp 1639ndash1662 1998

[37] T A Halgren ldquoCharacterization of MMFF94 MMFF94s andother widely available force fields for conformational energiesand for intermolecular-interaction energies and geometriesrdquoJournal of Computational Chemistry vol 20 1999

[38] C Y Chung H Y Chung W T Sung et al ldquoMoleculardocking for protein folding structure and drug-likenessprediction WSEAS conferencerdquo International Journal ofBiology and Biomedicine vol 1 pp 57ndash63 2005

[39] G Li H Zhou Y Jiang et al ldquoDesign and synthesis of 4-arylpiperidinyl amide and N-arylpiperdin-3-yl-cyclopropanecarboxamide derivatives as novel melatonin receptor ligandsrdquoBioorganic amp Medicinal Chemistry Letters vol 21 no 4pp 1236ndash1242 2011

[40] F J Solis and R J B Wets ldquoMinimization by random searchtechniquesrdquoMathematics of Operations Research vol 6 no 1pp 19ndash30 1981

[41] I A Alswaidan K Sooknah L Rhyman et al ldquo2 4-Ditel-lurouracil and its 5-fluoro derivative )eoretical investiga-tions of structural energetics and ADME parametersrdquoComputational Biology and Chemistry vol 68 pp 56ndash632017

16 Evidence-Based Complementary and Alternative Medicine

[42] M F Fromm ldquoP-glycoprotein a defense mechanism limitingoral bioavailability and CNS accumulation of drugsrdquo Inter-national Journal of Clinical Pharmacology amp Eerapeuticsvol 38 no 2 pp 69ndash74 2000

[43] G Szakacs A Varadi C Ozvegy Laczka and B Sarkadi ldquo)erole of ABC transporters in drug absorption distributionmetabolism excretion and toxicity (ADME-Tox)rdquo Drug Dis-covery Today vol 13 no 9-10 pp 379ndash393 2008

[44] B Testa and S D Kraemer ldquo)e biochemistry of drugmetabolism an introduction part 2 Redox reactions and theirenzymesrdquo ChemInform vol 38 no 23 pp 257ndash405 2007

[45] S Meeran V Baskar S Syed Tajudeen and T K ShabeerldquoDesign ADME profiling and molecular docking simulationof new isoniazid schiff base analogs as MtKasB InhibitorsrdquoAsian Journal of Chemistry and Pharmaceutical Science vol 6pp 20ndash34 2018

[46] J B Baell and G A Holloway ldquoNew substructure filters forremoval of pan assay interference compounds (PAINS) fromscreening libraries and for their exclusion in bioassaysrdquoJournal of Medicinal Chemistry vol 53 no 7 pp 2719ndash27402010

[47] T J Ritchie P Ertl and R Lewis ldquo)e graphical represen-tation of ADME-related molecule properties for medicinalchemistsrdquo Drug Discovery Today vol 16 no 1-2 pp 65ndash722011

[48] Z M Dastjerdi F Namjoyan and M E Azemi ldquoAlphaamylase inhibition activity of some plants extract of Teucriumspeciesrdquo European Journal of Biological Sciences vol 7pp 26ndash31 2015

[49] I M E Lacroix and E C Y Li-Chan ldquoOverview of foodproducts and dietary constituents with antidiabetic propertiesand their putative mechanisms of action a natural approachto complement pharmacotherapy in the management of di-abetesrdquo Molecular Nutrition amp Food Research vol 58 no 1pp 61ndash78 2014

[50] H V Rupasinghe S Sekhon-Loodu T Mantso andM I Panayiotidis ldquoPhytochemicals in regulating fatty acidβ-oxidation Potential underlying mechanisms and their in-volvement in obesity and weight lossrdquo Pharmacology ampEerapeutics vol 165 pp 153ndash163 2016

[51] M Qasim Z Abideen M Y Adnan et al ldquoAntioxidantproperties phenolic composition bioactive compounds andnutritive value of medicinal halophytes commonly used asherbal teasrdquo South African Journal of Botany vol 110pp 240ndash250 2017

[52] B Romano E Pagano V Montanaro A L FortunatoNMilic and F Borrelli ldquoNovel insights into the pharmacologyof flavonoidsrdquo Phytotherapy Research vol 27 pp 1588ndash15962013

[53] A P Rauter A Martins C Borges et al ldquoAntihyperglycaemicand protective effects of flavonoids on streptozotocinndashinduceddiabetic ratsrdquo Phytotherapy Research vol 24 pp S133ndashS1382010

[54] M O Agbo P F Uzor U N Nneji C U OdurukweU B Ogbatue and E C Mbaoji ldquoAntioxidant total phenolicand flavonoid content of selected Nigerian medicinal plantsrdquoDhaka University Journal of Pharmaceutical Science vol 14pp 35ndash41 2015

[55] N Saeed M R Khan and M Shabbir ldquoAntioxidant activitytotal phenolic and total flavonoid contents of whole plantextracts Torilis leptophylla Lrdquo BMC Complementary andAlternative Medicine vol 12 no 1 p 221 2012

[56] M R Kumbhare V Guleha and T Sivakumar ldquoEstimationof total phenolic content cytotoxicity and inndashvitro

antioxidant activity of stem bark of Moringa oleiferardquo AsianPacific Journal of Tropical Disease vol 2 pp 144ndash150 2012

[57] A A Ala B B Olotu and C M D Ohia ldquoAssessment ofcytotoxicity of leaf extracts of andrographis paniculata andaspilia Africana onmurine cellsrdquoArchives of basic and appliedmedicine vol 6 pp 61ndash65 2018

[58] S K Doreddula S R Bonam D P Gaddam B S R DesuN Ramarao and V Pandy ldquoPhytochemical analysis antioxi-dant antistress and nootropic activities of aqueous andmethanolic seed extracts of ladies finger (Abelmoschus escu-lentus L) in micerdquo Ee Scientific World Journal vol 2014Article ID 519848 14 pages 2014

[59] L A Nistor Baldea L C Martineau A Benhaddou-Anda-loussi J T Arnason E Levy and P S Haddad ldquoInhibition ofintestinal glucose absorption by anti-diabetic medicinal plantsderived from the James Bay Cree traditional pharmacopeiardquoJournal of Ethnopharmacology vol 132 no 2 pp 473ndash4822010

[60] N Shehzadi K Hussain N I Bukhari et al ldquoHypoglycemichepatoprotective and molecular docking studies of 5-[(4-chlorophenoxy) methyl]-1 3 4- oxadiazole-2-thiolrdquo Ban-gladesh Journal of Pharmacology vol 13 no 2 pp 149ndash1562018

[61] D Seeliger B L de Groot and V De Pymol ldquoLigand dockingand binding site analysis with PyMOL and AutodockVinardquoJournal of Computer-Aided Molecular Design vol 24pp 417ndash422 2010

[62] W Benalla S Bellahcen and M Bnouham ldquoAntidiabeticmedicinal plants as a source of alpha glucosidase inhibitorsrdquoCurrent Diabetes Reviews vol 6 no 4 pp 247ndash254 2010

[63] R Andleeb M U Ijaz A Rafique et al ldquoBiological activitiesof methanolic extract of aegle marmelos against HN protein ofnewcastle disease virusrdquo Agronomy vol 11 no 9 p 17842021

Evidence-Based Complementary and Alternative Medicine 17

[42] M F Fromm ldquoP-glycoprotein a defense mechanism limitingoral bioavailability and CNS accumulation of drugsrdquo Inter-national Journal of Clinical Pharmacology amp Eerapeuticsvol 38 no 2 pp 69ndash74 2000

[43] G Szakacs A Varadi C Ozvegy Laczka and B Sarkadi ldquo)erole of ABC transporters in drug absorption distributionmetabolism excretion and toxicity (ADME-Tox)rdquo Drug Dis-covery Today vol 13 no 9-10 pp 379ndash393 2008

[44] B Testa and S D Kraemer ldquo)e biochemistry of drugmetabolism an introduction part 2 Redox reactions and theirenzymesrdquo ChemInform vol 38 no 23 pp 257ndash405 2007

[45] S Meeran V Baskar S Syed Tajudeen and T K ShabeerldquoDesign ADME profiling and molecular docking simulationof new isoniazid schiff base analogs as MtKasB InhibitorsrdquoAsian Journal of Chemistry and Pharmaceutical Science vol 6pp 20ndash34 2018

[46] J B Baell and G A Holloway ldquoNew substructure filters forremoval of pan assay interference compounds (PAINS) fromscreening libraries and for their exclusion in bioassaysrdquoJournal of Medicinal Chemistry vol 53 no 7 pp 2719ndash27402010

[47] T J Ritchie P Ertl and R Lewis ldquo)e graphical represen-tation of ADME-related molecule properties for medicinalchemistsrdquo Drug Discovery Today vol 16 no 1-2 pp 65ndash722011

[48] Z M Dastjerdi F Namjoyan and M E Azemi ldquoAlphaamylase inhibition activity of some plants extract of Teucriumspeciesrdquo European Journal of Biological Sciences vol 7pp 26ndash31 2015

[49] I M E Lacroix and E C Y Li-Chan ldquoOverview of foodproducts and dietary constituents with antidiabetic propertiesand their putative mechanisms of action a natural approachto complement pharmacotherapy in the management of di-abetesrdquo Molecular Nutrition amp Food Research vol 58 no 1pp 61ndash78 2014

[50] H V Rupasinghe S Sekhon-Loodu T Mantso andM I Panayiotidis ldquoPhytochemicals in regulating fatty acidβ-oxidation Potential underlying mechanisms and their in-volvement in obesity and weight lossrdquo Pharmacology ampEerapeutics vol 165 pp 153ndash163 2016

[51] M Qasim Z Abideen M Y Adnan et al ldquoAntioxidantproperties phenolic composition bioactive compounds andnutritive value of medicinal halophytes commonly used asherbal teasrdquo South African Journal of Botany vol 110pp 240ndash250 2017

[52] B Romano E Pagano V Montanaro A L FortunatoNMilic and F Borrelli ldquoNovel insights into the pharmacologyof flavonoidsrdquo Phytotherapy Research vol 27 pp 1588ndash15962013

[53] A P Rauter A Martins C Borges et al ldquoAntihyperglycaemicand protective effects of flavonoids on streptozotocinndashinduceddiabetic ratsrdquo Phytotherapy Research vol 24 pp S133ndashS1382010

[54] M O Agbo P F Uzor U N Nneji C U OdurukweU B Ogbatue and E C Mbaoji ldquoAntioxidant total phenolicand flavonoid content of selected Nigerian medicinal plantsrdquoDhaka University Journal of Pharmaceutical Science vol 14pp 35ndash41 2015

[55] N Saeed M R Khan and M Shabbir ldquoAntioxidant activitytotal phenolic and total flavonoid contents of whole plantextracts Torilis leptophylla Lrdquo BMC Complementary andAlternative Medicine vol 12 no 1 p 221 2012

[56] M R Kumbhare V Guleha and T Sivakumar ldquoEstimationof total phenolic content cytotoxicity and inndashvitro

antioxidant activity of stem bark of Moringa oleiferardquo AsianPacific Journal of Tropical Disease vol 2 pp 144ndash150 2012

[57] A A Ala B B Olotu and C M D Ohia ldquoAssessment ofcytotoxicity of leaf extracts of andrographis paniculata andaspilia Africana onmurine cellsrdquoArchives of basic and appliedmedicine vol 6 pp 61ndash65 2018

[58] S K Doreddula S R Bonam D P Gaddam B S R DesuN Ramarao and V Pandy ldquoPhytochemical analysis antioxi-dant antistress and nootropic activities of aqueous andmethanolic seed extracts of ladies finger (Abelmoschus escu-lentus L) in micerdquo Ee Scientific World Journal vol 2014Article ID 519848 14 pages 2014

[59] L A Nistor Baldea L C Martineau A Benhaddou-Anda-loussi J T Arnason E Levy and P S Haddad ldquoInhibition ofintestinal glucose absorption by anti-diabetic medicinal plantsderived from the James Bay Cree traditional pharmacopeiardquoJournal of Ethnopharmacology vol 132 no 2 pp 473ndash4822010

[60] N Shehzadi K Hussain N I Bukhari et al ldquoHypoglycemichepatoprotective and molecular docking studies of 5-[(4-chlorophenoxy) methyl]-1 3 4- oxadiazole-2-thiolrdquo Ban-gladesh Journal of Pharmacology vol 13 no 2 pp 149ndash1562018

[61] D Seeliger B L de Groot and V De Pymol ldquoLigand dockingand binding site analysis with PyMOL and AutodockVinardquoJournal of Computer-Aided Molecular Design vol 24pp 417ndash422 2010

[62] W Benalla S Bellahcen and M Bnouham ldquoAntidiabeticmedicinal plants as a source of alpha glucosidase inhibitorsrdquoCurrent Diabetes Reviews vol 6 no 4 pp 247ndash254 2010

[63] R Andleeb M U Ijaz A Rafique et al ldquoBiological activitiesof methanolic extract of aegle marmelos against HN protein ofnewcastle disease virusrdquo Agronomy vol 11 no 9 p 17842021

Evidence-Based Complementary and Alternative Medicine 17