EFEK ESTERIFIKASI GUGUS –OH SENYAWA (2,5-BIS(4-HIDROKSI-3- METOKSIBENZILIDIN)-SIKLOPENTANON) DAN (2,5-BIS(4-HIDROKSI Efek Esterifikasi Gugus –Oh Senyawa (2,5-Bis(4-Hidroksi-3-Metoksibenzilidin)-Siklopentanon) Dan (2,5-Bis(4-Hidroksi -3,5-Dimetil)-Benzili
EFEK ESTERIFIKASI GUGUS –OH SENYAWA (2,5-BIS(4-HIDROKSI-3METOKSIBENZILIDIN)-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
EFEK ESTERIFIKASI GUGUS –OH SENYAWA (2,5-BIS(4-HIDROKSI-3METOKSIBENZILIDIN)-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
ii
iii
iv
v
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
vi
A. Kesimpulan ................................................................................................ 22
B. Saran ........................................................................................................... 22
DAFTAR PUSTAKA ........................................................................................... 23
vii
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
viii
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
ix
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
x
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
xi
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
xii
ABSTRAK
2,5-bis(4-hidroksi-3-Metoksibenzilidin)-siklopentanon dan 2,5-bis(4hidroksi-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 PyRxVina AutoDock. Ligan uji yang digunakan adalah 2,5-bis(4-asetiloksi-3Metoksibenzilidin)-siklopentanon
dan
2,5-bis(4-asetiloksi-3,5-dimetil)benzilidinsiklopentanon. Ligan pembanding yang digunakan adalah 2,5-bis(4hidroksi-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(4hidroksi-3,5-dimetil)-benzilidinsiklo-pentanon;
2,5-bis(4-asetiloksi-3Metoksibenzilidin)-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(4hidroksi-3,5-dimetil)-benzilidinsiklopentanon, Molecular Docking , PyRx VinaAutodock
xiii
ABSTRACT
2,5-bis (4-hydroxy-3-Methoxybenzylidene)-cyclopentanone and 2,5-bis (4hydroxy-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 PyRxVina Autodock. Ligands of test used were 2,5-bis (4-acetyloxy-3Methoxybenzylidene) -cyclopentanone and 2,5-bis (4-acetyloxy-3,5-dimethyl)benzylidenecyclopentanone. Ligands of standard used were 2,5-bis (4-hydroxy-3Metoxybenzylidene)-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)-benzylidenecyclopentanone; 2,5-bis (4-hydroxy-3,5-dimethyl)-benzylidene-cyclopentanone;
2,5-bis (4-acetyloxy-3-Methoxybenzylidene)-cyclopentanone; 2,5-bis (4-hydroxy3-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 (4hydroxy-3,5-dimethyl) -benzilidincyclopentanone, Molecular Docking, PyRx
Vina-Autodock
xiv
-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
EFEK ESTERIFIKASI GUGUS –OH SENYAWA (2,5-BIS(4-HIDROKSI-3METOKSIBENZILIDIN)-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
ii
iii
iv
v
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
vi
A. Kesimpulan ................................................................................................ 22
B. Saran ........................................................................................................... 22
DAFTAR PUSTAKA ........................................................................................... 23
vii
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
viii
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
ix
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
x
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
xi
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
xii
ABSTRAK
2,5-bis(4-hidroksi-3-Metoksibenzilidin)-siklopentanon dan 2,5-bis(4hidroksi-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 PyRxVina AutoDock. Ligan uji yang digunakan adalah 2,5-bis(4-asetiloksi-3Metoksibenzilidin)-siklopentanon
dan
2,5-bis(4-asetiloksi-3,5-dimetil)benzilidinsiklopentanon. Ligan pembanding yang digunakan adalah 2,5-bis(4hidroksi-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(4hidroksi-3,5-dimetil)-benzilidinsiklo-pentanon;
2,5-bis(4-asetiloksi-3Metoksibenzilidin)-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(4hidroksi-3,5-dimetil)-benzilidinsiklopentanon, Molecular Docking , PyRx VinaAutodock
xiii
ABSTRACT
2,5-bis (4-hydroxy-3-Methoxybenzylidene)-cyclopentanone and 2,5-bis (4hydroxy-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 PyRxVina Autodock. Ligands of test used were 2,5-bis (4-acetyloxy-3Methoxybenzylidene) -cyclopentanone and 2,5-bis (4-acetyloxy-3,5-dimethyl)benzylidenecyclopentanone. Ligands of standard used were 2,5-bis (4-hydroxy-3Metoxybenzylidene)-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)-benzylidenecyclopentanone; 2,5-bis (4-hydroxy-3,5-dimethyl)-benzylidene-cyclopentanone;
2,5-bis (4-acetyloxy-3-Methoxybenzylidene)-cyclopentanone; 2,5-bis (4-hydroxy3-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 (4hydroxy-3,5-dimethyl) -benzilidincyclopentanone, Molecular Docking, PyRx
Vina-Autodock
xiv