EFEK ESTERIFIKASI GUGUS –OH SENYAWA (2,5-BIS(4-HIDROKSI-3-

METOKSIBENZILIDIN)-SIKLOPENTANON) DAN (2,5-BIS(4-HIDROKSI

-3 ,5-DIMETIL)-BENZILIDINSIKLOPENTANON)TERHADAP INHIBISI

PROTEIN TUBULIN HOMOLOG PADA ANTI KANKER DENGAN

MOLECULAR DOCKING PyRx

SKRIPSI

Oleh:

NURUL FAKHMI

K 100 120 027

FAKULTAS FARMASI

UNIVERSITAS MUHAMMADIYAH SURAKARTA

SURAKARTA

2016

ii

EFEK ESTERIFIKASI GUGUS –OH SENYAWA (2,5-BIS(4-HIDROKSI-3-

METOKSIBENZILIDIN)-SIKLOPENTANON) DAN (2,5-BIS(4-HIDROKSI

-3 ,5-DIMETIL)-BENZILIDINSIKLOPENTANON)TERHADAP INHIBISI

PROTEIN TUBULIN HOMOLOG PADA ANTI KANKER DENGAN

MOLECULAR DOCKING PyRx

HALAMAN SAMPUL

SKRIPSI

Diajukan untuk memenuhi salah satu syarat mencapai Sarjana

Farmasi (S. Farm) pada Fakultas Farmasi Universitas

Muhammadiyah Surakarta

di Surakarta

Oleh:

NURUL FAKHMI

K100 120 027

FAKULTAS FARMASI

UNIVERSITAS MUHAMMADIYAH SURAKARTA

SURAKARTA

2016

iii

iv

v

vi

DAFTAR ISI

HALAMAN SAMPUL ........................................................................................... ii

HALAMAN PENGESAHAN ................................................................................ iii

DEKRALASI ......................................................................................................... iv

KATA PENGANTAR ............................................................................................ v

DAFTAR ISI .......................................................................................................... vi

DAFTAR GAMBAR ........................................................................................... viii

DAFTAR TABEL .................................................................................................. ix

DAFTAR LAMPIRAN ........................................................................................... x

DAFTAR SINGKATAN ....................................................................................... xi

ABSTRAK ........................................................................................................... xiii

BAB I. PENDAHULUAN ...................................................................................... 1

A. Latar Belakang ............................................................................................. 1

B. Rumusan Masalah ........................................................................................ 2

C. Tujuan Penelitian ......................................................................................... 2

D. Tinjauan Pustaka .......................................................................................... 3

1. Pentagamavunon (PGV) ........................................................................... 3

2. Siklus Sel .................................................................................................. 4

3. ProteinTubulin .......................................................................................... 6

4. Molecular Docking ................................................................................... 6

E. Landasan Teori ............................................................................................. 7

F. Hipotesis ....................................................................................................... 8

BAB II. METODE PENELITIAN .......................................................................... 9

A. Jenis Penelitian ............................................................................................. 9

B. Variabel Penelitian ....................................................................................... 9

C. Alat dan Bahan ........................................................................................... 10

D. Tempat Penelitian....................................................................................... 10

E. Jalannya Penelitian ..................................................................................... 11

BAB III. HASIL DAN PEMBAHASAN.............................................................. 12

BAB IV. KESIMPULAN DAN SARAN ............................................................. 22

vii

A. Kesimpulan ................................................................................................ 22

B. Saran ........................................................................................................... 22

DAFTAR PUSTAKA ........................................................................................... 23

viii

DAFTAR GAMBAR

Gambar 1. Struktur Ligan Uji Sumber diambil dari MarvinSketch ........................ 3

Gambar 2. Siklus Pembelahan sel (Campbell et al., 2010) ..................................... 5

Gambar 3. Pembelahan sel normal (Campbell et al., 2010) ................................... 6

Gambar 4. Grid box pocket terbesar ..................................................................... 15

Gambar 5. Hasil Visualisasi 2D ............................................................................ 18

Gambar 6. Hasil visualisasi Ligan dengan residu ................................................ 21

Gambar 7. Hasil Visualisai Asam amino .............................................................. 22

ix

DAFTAR TABEL

Tabel 1. Fasta protein tubulin manusia .................................................................. 13

Tabel 2. Hasil Pencarian Homolog Tubulin ........................................................... 14

Tabel 3. Nilai binding affinity (kkal/mol) dan binding energy (kkal/mol) hasil

docking ligan uji dan ligan pembanding terhadap protein Homolog

tubulin ......................................................................................................... 17

Tabel 4. Nilai binding affinity (kkal/mol) dan binding energy (kkal/mol) hasil

docking ligan MIMICs dengan protein Homolog tubulin .......................... 18

Tabel 5. Interaksi antara ligan uji dan pembanding dengan residu pada protein

Homolog tubulin ......................................................................................... 19

x

DAFTAR LAMPIRAN

Lampiran 1. Hasil Score Molecular Docking Senyawa dengan Metode Vina .... 27

Lampiran 2. Hasil Score Molecular Docking Senyawa dengan Metode LGA .... 29

Lampiran 3. Hasil Score Molecular Docking Senyawa dengan Metode GA ...... 31

Lampiran 4. Hasil Score Molecular Docking Senyawa dengan Metode SA ....... 33

xi

DAFTAR SINGKATAN

3D : 3 Dimensi

Å : Angstrom

ALA : Alanin

ARG : Arginin

CPU : Central Processing Unit

GLN : Glutamin

GLY : Glisin

HIS : Histidin

ILE : Isoleusin

LEU : Leusin

PDB : Protein Data Bank

PHE : Fenilalanin

PLIP : Protein Data Interaction Profiler

RAM : Random Access Memory

SER : Serin

TYR : Tirosin

VAL : Valin

SER : Serin

LYS : Lisin

MET : Metionin

ASN : Asparagin

PRO : Prolin

GLU : Asam glutamat

ASP : Asam aspartat

xii

GDP : Guanosine-5'-Diphospate

LGA : Lamarckian Genetic Algorithm

GA : Genetic Algorithm

SA : Simulated Annealing

TRP : Triptofan

THR : Treonin

MES : 2-(N-Morpholino)-Ethanesulfoni

GHz : Gigaherzt

GB : Gigabyte

xiii

ABSTRAK

2,5-bis(4-hidroksi-3-Metoksibenzilidin)-siklopentanon dan 2,5-bis(4-

hidroksi-3,5-dimetil)-benzilidinsiklopentanon merupakan senyawa-senyawa yang

memiliki aktivitas antikanker lebih baik dibandingkan dengan kurkumin. Kedua

senyawa tersebut memiliki kepolaran yang rendah. Melalui esterifikasi pada

gugus –OH, kepolaran senyawa tersebut dapat ditingkatkan. Tujuan dari

penelitian ini adalah untuk mengetahui pengaruh esterifikasi terhadap peningkatan

aktivitas penghambatan protein tubulin melalui metode molecular docking.

Homolog protein tubulin dipreparasi dan divalidasi menggunakan PyRx-

Vina AutoDock. Ligan uji yang digunakan adalah 2,5-bis(4-asetiloksi-3-

Metoksibenzilidin)-siklopentanon dan 2,5-bis(4-asetiloksi-3,5-dimetil)-

benzilidinsiklopentanon. Ligan pembanding yang digunakan adalah 2,5-bis(4-

hidroksi-3-Metoksibenzilidin)-siklopentanon dan 2,5-bis(4-hidroksi-3,5-dimetil)-

benzilidinsiklo-pentanon, Kurkumin, Vinkristine, Vinblastine dan ligan MIMICs

sebanyak 200 senyawa. Molecular docking ligan-ligan dilakukan menggunakan

Vina dan Autodock dengan metode Lamarckian Genetic Algorithm (LGA),

Genetic Algorithm (GA), dan Simulated Annealing (SA). Hasil dianalisis

menggunakan PLIP.

Hasil analisis menunjukan urutan binding affinity ligan (kecil ke besar) sebagai

berikut 2,5-bis(4-asetiloksi-3,5-dimetil)-benzilidinsiklopentanon; 2,5-bis(4-

hidroksi-3,5-dimetil)-benzilidinsiklo-pentanon; 2,5-bis(4-asetiloksi-3-

Metoksibenzilidin)-siklopentanon; 2,5-bis(4-hidroksi-3-metoksi-benzilidin)-

siklopentanon; Kurkumin; Vinblastine; dan Vinkristine. Dengan demikian dapat

disimpulkan bahwa esterifikasi menyebabkan kenaikan peningkatan aktivitas

antikanker melalui penurunan binding affinity dan binding energy dan

peningkatan interaksi asam amino.

Kata Kunci : 2,5-bis(4-hidroksi-3-Metoksibenzilidin)-siklopentanon, 2,5-bis(4-

hidroksi-3,5-dimetil)-benzilidinsiklopentanon, Molecular Docking , PyRx Vina-

Autodock

xiv

ABSTRACT

2,5-bis (4-hydroxy-3-Methoxybenzylidene)-cyclopentanone and 2,5-bis (4-

hydroxy-3,5-dimethyl)-benzylidenecyclopentanone were compounds that had

known better anticancer activity than curcumin but lack of polarity. Through

esterification in -OH groups, the polarity of these compounds can be improved.

The aims to determine the effect of esterification on increasing activity of the

inhibition of tubulin protein by molecular docking method.

Homologs of tubulin protein were prepared and validated using PyRx-

Vina Autodock. Ligands of test used were 2,5-bis (4-acetyloxy-3-

Methoxybenzylidene) -cyclopentanone and 2,5-bis (4-acetyloxy-3,5-dimethyl)-

benzylidenecyclopentanone. Ligands of standard used were 2,5-bis (4-hydroxy-3-

Metoxybenzylidene)-cyclopentanone and 2,5-bis (4-hydroxy-3,5-dimethyl)-

benzylidenecyclopentanone, Curcumin, Vinkristine, Vinblastine and ligand of

mimics as many as 200 compounds. Molecular docking of ligands were performed

using Vina and Autodock through methods of Lamarckian Genetic Algorithm

(LGA), Genetic Algorithm (GA) and Simulated Annealing (SA), then analyzed

using PLIP.

The results showed that the sequence of binding affinity of ligands (small

to large) as follows 2,5-bis (4-acetyloxy-3,5-dimethyl)-benzylidene-

cyclopentanone; 2,5-bis (4-hydroxy-3,5-dimethyl)-benzylidene-cyclopentanone;

2,5-bis (4-acetyloxy-3-Methoxybenzylidene)-cyclopentanone; 2,5-bis (4-hydroxy-

3-Metoxybenzylidene)-cyclopentanone; curcumin; vinblastine; and Vinkristine.

Therefore it can be concluded that esterification lead to increase anticancer

activity through decreasing binding affinity and binding energy and increasing

amino acid interaction.

Keywords: 2,5-bis(4-hydroxy-3-Methoxybenzilidin)-cyclopentanone, 2,5-bis (4-

hydroxy-3,5-dimethyl) -benzilidincyclopentanone, Molecular Docking, PyRx

Vina-Autodock