A review article on- Molecular pharmacology

International Journal of Pharmaceutical and Medical Sciences ISSN 2319-1252

Original Review Article Available online at www.ijpms.com Vol. 1(3), Oct.-Dec. 2012

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MOLECULAR PHARMACOLOGY: ROLE IN

INDIVIDUALIZED MEDICINES

Ratnere Taruna1*, Sharma Praveen

1

1. College of Pharmacy, IPS Academy, Rajendra Nagar, Indore (M.P.), India

Corresponding author: [email protected]

Abstract

Molecular pharmacology is a branch of the field of pharmacology which is concerned with the

study of pharmacology on a molecular basis. Understanding biology at the molecular and

systems levels will require new approaches to biomedical research, including the integration of

quantitative, chemical, and biological methods. The next generation of scientists must be capable

of bridging these diverse disciplines. Molecular modeling is one key method of a wide range of

computer-assisted methods to analyze and predict relationships between protein sequence, 3D-

molecular structure, and biological function (sequence–structure–function-relationships). In

molecular pharmacology these methods focus predominantly on analysis of interactions between

different proteins, and between ligands (hormones, drugs) and proteins as well as gaining

information at the amino acid and even to atomic level.

Keywords

Molecular modeling, Orexin, Molecular Biology, Structural Bioinformatics.



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Introduction

Molecular pharmacology is a branch of the field of pharmacology which is concerned with the

study of pharmacology on a molecular basis. Molecular pharmacologists study the molecular

study of pharmaceuticals and natural compounds used in the treatment of disease, and they also

study disease on a molecular basis with the goal of developing pharmacologically active agents

which could be used to address disease. Employment in this field is generally limited to people

who hold graduate degrees, often with post-doctoral work in the field.

One of the most important aspects of molecular pharmacology understands how drugs work on a

molecular basis. For a patient who takes antibiotics for an infection, the molecular explanation

for the efficacy of the drugs might not seem terribly important, as long as they work, but for

molecular pharmacologists, it's critical. A molecular pharmacologist can find out how the drug

attacks the bacteria causing the infection, how the bacteria develops antibiotic resistance, and

how a drug company might develop a new antibiotic which targets an antibiotic-resistant bacteria

on the molecular level.

Molecular pharmacologists are also interested in molecular pathology, the study of the process of

disease on a molecular level. This is especially relevant with malignancies which develop

spontaneously, as an understanding of how much malignancies emerge could be a key part to

developing drugs which will target these malignancies. Researchers in molecular pharmacology

are also interested in developing highly refined drugs which are capable of attacking a

malignancy and nothing else, thereby reducing side effects for the patient.

Understanding the molecular structure of drugs is also important. From the point of view of

pharmaceutical companies, knowing as much as possible about their drugs is useful because it

can help them protect patents, develop similar drugs, organize drug families, and understand

drug actions. For researchers, knowing the molecular structure of a drug is important for many of

the same reasons. People can approach this field from a number of angles within the biological

sciences. Some colleges and universities offer molecular pharmacology degrees to their students,

and these degrees can include a high level of personalization to the student's interests and needs.



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Generally, coursework in molecular pharmacology includes topics like biology, anatomy,

physiology, molecular chemistry, and other fields within the biological sciences [1, 2, 3].

Molecular Modeling

Molecular modeling itself can be simply described as the computer-assisted calculation,

modulation, and visualization of realistic 3D-molecular structures and their physical–chemical

properties.

Molecular modeling is one key method of a wide range of computer-assisted methods to analyse

and predict relationships between protein sequence, 3D-molecular structure, and biological

function (sequence–structure–function-relationships). In molecular pharmacology these methods

focus predominantly on analysis of interactions between different proteins, and between ligands

(hormones, drugs) and proteins as well as gaining information at the amino acid and even to

atomic level [4].

Structure–Function Prediction

From the human genome project it is known, that roughly 30,000 proteins exist in humans.

Currently only the 3D-structures of few thousand human protein or protein domains are known.

Structures of membrane bound proteins are several magnitudes rarer. Beside efforts to solve

further structures like structural genomics, there is a challenge for computational approaches to

predict structures and function for homologous proteins [5].



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Fig. 1: Molecular model image of the environment of ECL2 in the wild type Thyroid stimulating

hormone receptor.

Retinoids

Vitamin A (retinol) and its naturally occurring and synthetic derivatives, collectively referred to

as retinoids (chemical structure), exert a wide variety of profound effects in apoptosis,

embryogenesis, reproduction, vision, and regulation of inflammation, growth, and differentiation

of normal and neoplastic cells in vertebrates. Retinoids mediate their biological effects through

binding to nuclear receptors known as retinoic acid receptors (RARs) and retinoid X receptors

(RXRs), which belong to the superfamily of ligand-inducible transciptional regulators that

include steroid hormone receptors, thyroid hormone receptors, and vitamin D3 receptors [6]. The

known beneficial effects of retinoids on malignancies are assumed to relate to retinoid receptor

mediated anti-promoting and- anti-initiating effects. The latter appears to be influenced by

interference of several xenobiotics with different steps of the retinoid metabolism in the target

cell. Of the carotenoids, β-carotene is the most potent retinol precursor, yet being six-fold less

effective than preformed retinol, resulting from incomplete resorption and conversion.

ANTHRACYCLINES

The anthracyclines represent a broad family of antibiotics that exhibit activity in numerous

tumors. The first anthracyclines, doxorubicin (DOX) and daunorubicin (DNR), were isolated



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from Streptomyces var peucetius. DOX and other approved anthracyclines have long been

known to inhibit topoisomerase II (topo II). This enzyme promotes the formation of double-

strand DNA breaks, which are resealed after changing the twisting status of the double helix of

DNA. Topo II is highly important to proliferating cells, as the supercoiling of the DNA double

helix is modulated according to the cell cycle phase and transcriptional activity. Anthracyclines

stabilize a reaction intermediate in which DNA strands are cut and covalently linked to topo II,

eventually impeding DNA resealing.

The novel anthracyclines or related anthraquinones offered only modest advantages over DOX-

EPI or DNR-IDA, with the possible exceptions being nemorubicin (for the locoregional

treatment of hepatocellular carcinoma), pixantrone (for the second-line treatment of non-

Hodgkin’s lymphomas), sabarubicin (for the treatment of non-small cell lung cancer, hormone

refractory metastatic prostate cancer, platinum- or taxane-resistant ovarian cancer), valrubicin

(for the topical treatment of bladder cancer) [7].

CAMPTOTHECIN

Camptothecin is a plant alkaloid that selectively targets topoisomerase I (Top1). It produces

DNA damage leading to the destruction of eukaryotic cells. Because 314- Calsequestrin of

selectivity against cancer cells, camptothecin derivatives are used as anticancer drugs.

Camptothecin comes from Camptotheca acuminata, a deciduous tree found in southern China.

Stem woods of Nothopodytes foetida found in the Western Ghats of India are an even better

source of camptothecin.

The natural isomer of camptothecin: 20-S-camptothecin is a highly specific Top1 inhibitor. Top1

is the only cellular target of camptothecins as human cell lines selected for drug resistance

consistently mutate their Top1 in such a way that those mutant enzymes become highly resistant

to camptothecins while remaining catalytically active. TOP1 is an essential gene in metazoans

whereas yeast strains with TOP1 gene deletion are viable but immune to camptothecins [8].

Topotecan (Hycamtin®): is routinely used to treat ovarian cancers and small-cell-lung cancers

(SCLC). It is given by intravenous infusion. Hematological toxicity is a common side effect due



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to the destruction of bone marrow progenitors. Irinotecan (CPT-11): is approved for colorectal

tumors. It is given by intravenous infusion. The most severe side effect is diarrhoea, which can

be severe and needs to be treated by a physician.

GLUCO-MINERALOCORTICOID RECEPTOR

Glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) are members of the nuclear

receptor superfamily and they mediate the organisms response to cortisol and aldosterone, two

steroid hormones synthesized in the adrenal gland. GR is ubiquitously expressed and orchestrates

a plethora of physiological processes including energy homeostasis, stress response, and

inflammation. In contrast, expression of MR is largely restricted to epithelial cells in kidney and

colon as well as the limbic system of the brain [9,10].

Drugs: GR Ligands

Glucocorticoid agonists mainly comprise cortisol, corticosterone, aldosterone, and

synthetic steroids used in clinical therapy such as dexamethasone, prednisolone,

methylprednisolone, or triamcinolone.

In addition, also some non-steroidal compounds such as aziridines may bind to GR and

regulate its activity. Agonists are defined as compounds, which bind to the receptor and

elicit a transcriptional response. Cortisol and corticosterone have equal affinities for GR.

▶RU486 (Mifepristone), which also binds to progesterone receptor, and the unrelated

compound ZK98299, a presumably pure GR ligand [11].

MR Ligands

MR has a high affinity for mineralocorticoids such as aldosterone and DOC.

Mineralo-corticoid agonist in humans is aldosterone. Additionally, cortisol,

corticosterone, and DOC have also mineralocorticoid agonistic activity. The synthetic

steroid fludrocortisone is extremely potent and usually chosen for replacement

mineralocorticoid therapy.



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Mineralocorticoid antagonists include RU26752, spironolactone, epelerone, and

progesterone.

Whereas endogenous progesterone may only play a role during the third trimester of

pregnancy, spironolactone, epelerone, and RU26752 are synthetic drugs [12].

INSULIN RECEPTOR

The insulin receptor is a trans-membrane receptor tyrosine kinase located in the plasma

membrane of insulin-sensitive cells (e.g., adipocytes, myocytes, hepatocytes). It mediates the

effect of insulin on specific cellular responses (e.g., glucose transport, glycogen synthesis, lipid

synthesis, protein synthesis). Stimulation of the insulin receptor results in the activation of two

major pathways:

The mitogen activated protein (MAP) kinase cascade.

The phosphatidylinositol 3-kinase (PI 3-kinase) pathway.

Agents Inhibiting Insulin Receptor Signaling

Insulin-Analogs: Several covalently dimerized insulin analogs are partial agonists of the insulin

receptor. The intrinsic activity of the dimers decreases with the length of the spacer, with B29-

B29’- suberoyl-insulin exhibiting the highest antagonist efficacy at the receptor.

Wortmannin is a fungus-derived inhibitor of PI 3-kinase. The agent binds and inhibits the

enzyme covalently and irreversibly. It is very potent and considered to be highly specific.

Rapamycin is an immunosuppressive drug and an inhibitor of S6K1 which phosphorylates

ribosomal S6 protein. Rapamycin binds to a specific target protein (mTOR, mammalian target of

rapamycin) which is functionally located downstream of Akt, but upstream of S6K1 [13,14].

OREXIN

Orexin-A (OX-A) and Orexin-B (OX-B) are bioactive peptides derived from a common

precursor gene. Both peptides bind with differential affinity to two Gq/11- protein coupled

receptors (OX1R, OX2R) in numerous targets throughout and even outside the nervous system



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of many species. Pharmacological targeting of the orexin receptors by selective OXR agonists or

antagonists could provide near causal therapy of narcolepsy-cataplexy, or efficient treatment of

insomnia, and possibly addiction, respectively. However, orally active, blood–brain barrier

permeable, small molecule OXR agonists are not yet available.

All drugs currently used to treat symptoms of narcolepsy-cataplexy thus mimic orexinergic

effects by interfering with aminergic (amphetamines, antidepressants, modafinil) and

GABAerigc (gamma-hydroxy butyrate) neurotransmission. Of the available prodrugs

antagonizing orexin receptor function only ACT-078573 has been tested in humans, so far.

ACT-078573 is an orally active, brain penetrating OX1/2R-antagonist and has been introduced as

an efficient sleep-promoting and possibly anti-addictive drug in rats, dogs, and humans. It lacks

unwanted side effects of GABAergic sedative substances (i.e., REM sleep suppression and

addiction) and did not produce cataplexy in humans after acute ingestion. This suggests that

other factors produced by orexin neurons (e.g., ▶NARP, dynorphin) may contribute to the

development of cataplexy, or chronic blockade ofOX1/2R-antagonists may be required to

produce cataplexy [15,16].

ANTI-PLATELET DRUGS

Platelets play a central role in primary hemostasis. They are also important in pathological

processes leading to thrombosis. Antiplatelet drugs are primarily directed against platelets and

inhibit platelet activation by a number of different mechanisms. They are used for the prevention

& treatment of thrombotic processes, especially in the arterial vascular system [17]. Platelet

adhesion, activation, aggregation and thrombus formation on sub-endothelial surface at an

injured blood vessel. After an injury of the vascular endothelium, the processes of primary

hemostasis (platelet activation) as well as of secondary hemostasis (fibrin formation via the

coagulation cascade) are triggered by a variety of stimuli. Shown are only the mechanisms of

primary hemostasis. Platelets adhere via their receptor GPIb-IX-V and GPVI mediated by von-

Willebrand factor (vWf) or binding of extracellular matrix (especially collagen) to the sub-

endothelium.



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Binding of collagen to GPVI initiates platelet activation resulting in integrin activation and the

formation of a variety of diffusible mediators like ADP, thromboxane A2 (TXA2) as well as

thrombin. These mediators initiate the second phase of platelet thrombus formation by recruiting

platelets from the blood stream into a growing platelet aggregate. The crosslinking of platelets

primarily involves the activated integrin αIIbβ3 (GPIIb/IIIa) which can bind the bivalent ligands

vWf and fibrinogen (Fb) resulting in the crosslinking of platelets.

Drugs:

Acetylsalicylic Acid (Aspirin):

TXA2 is produced by activated platelets via the sequential conversion of arachidonic acid by

phospholipase A2, cyclooxygenase-1 (COX-1), and thromboxane synthase. Low doses of

acetylsalicylic acid (aspirin) have an antiplatelet effect by inhibiting the TXA2 production by

irreversibly acetylating COX-1 at serine-530 close to the active site of the enzyme which

interferes with the binding of the substrate arachidonic acid to the enzyme. This results in

impaired platelet function for the rest of its lifespan (7–10 days).

Thienopyridines:

ADP is released from activated platelets by the secretion of dense granules and acts through at

least three receptors. These are the ionotropic purinoceptor 2X1 (P2X1) and two G-protein-

coupled receptors, the Gq-coupled purinoceptor 2Y1 (P2Y1), and the Gi-coupled P2Y12

receptor. The latter has also been termed P2TAC or P2cyc and is targeted by a group of

antiplatelet agents – the thienopyridines – such as ticlopidine and clopidogrel. To become

activated, ticlopidine and clopidogrel require biotransformation by the hepatic CYP3A4 enzyme

into active metabolites.

ANTI-VIRAL DRUGS

Antiviral drugs inhibit viral replication by specifically targeting viral enzymes or functions and

are used to treat specific virus-associated diseases. Most antivirals have been developed to

control chronic or recurrent virus infections, and in many cases antiviral treatment does not result



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in elimination of the virus but rather reduction of virus replication and alleviation of symptoms

[18, 19].

Clinical Use (Including Side Effects)

Infections with the herpesviruses HSV and VZV are treated with ACV, famciclovir or brivudin.

Intraveneous treatment is indicated for herpes virus encephalitis, neonatal HSV infection, and

HSV and VZV reactivation under immunosuppression.

Herpes genitalis and herpes zoster are treated orally, and topical ACV treatment is used

against herpes labialis. Alternative HSV and VZV treatment is possible using idoxuridine

or vidarabin.

Foscarnet can be used against resistant viruses but has a higher risk of side effects

(nephrotoxicity).

A combination therapy of IFN-α (“pegylated”, i.e., coupled to polyethylene glycol, which

prevents its rapid clearance from the body) and ribavirin over 24–48 weeks is the most

effective way to treat chronic hepatitis C.

AIDS patients in industrial countries are treated with a combination therapy known as

HAART (highly active antiretroviral therapy) involving at least three different anti-HIV

drugs [20].

CONCLUSION

The study of molecular pharmacology led to a reconsideration of the importance of system

pharmacology and in-vivo models, and indicates that the discovery of new medicines will require

a combination of the recently developed molecular tools and the effectiveness of the more

traditional approaches that study biological system as a whole. All the defined molecules,

although ‘big’ in terms of drug-ability, might represent more complex -3D structures that will

serve soon as pharmacological tools. Study of molecular pharmacology enables the identification

of new compounds that may be more efficacious or have reduced side effects.



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A review article on- Molecular pharmacology

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