VIRTUAL SCREENING COMPOUNDS IN PIPERACEAE PLANTS AS

LIGANDS TO ESTROGEN RECEPTOR ALPHA (ER-α)

Rodelaide Third International Conference on

Faculty of Pharmacy Pancasila University Pharmaceutical Nanotechnology/Nanomedicine 2017

Jakarta Indonesia October 9th,2017 Faculty of Pharmacy Pancasila

University Jakarta Indonesia

Family Piperaceae contains about 3,600 species currently divided into 13 genera. Some family Piperaceae plants are known to have activity as an anti-breast cancer. In this
. as Piper nigrum L, Piper methysticum, Piper cubeba L. f., Piper betle L, and Piper
research, the virtual screening of compound 2D structure of some family Piperaceae plants such
longum L. The purpose of this study was to analyze and obtain candidate compounds that active as ligand to ER-α using virtual screening protocols validated Anita et al (2012)
which then would be carried elucidation of representative compounds active bonding modes to see the interaction of amino acids in the binding site of these compounds. This
protocol uses the Linux operating system Ubuntu 10.04 LTS with integrated applications such as SPORES, PLANTS 1.2, BKChem, Open Babel, R Computational Statistics and
PyMOL, comparison compound 2-(4-hydroxy-phenyl)-1-(4-pyrolidin-1-yl-butyl)-1H-indol-5-ol or ZINC 01914469, reference compound 4- [4-hydroxy-3- (prop-2- en-1-yl)
phenyl] -2- (prop-2-en-1-yl) (dimer compound number 11 or ZINC 01,688,147) and 4-hidroksitamoksifen as a positive control. Results of virtual screening conducted on 110
compounds of five plant family Piperaceae obtained 2 compounds that considered active by comparison compound and 39 compounds are considered active by reference compound.
Four amino acid residues are considered instrumental to the affinity between the compound and the ER-α namely GLU353, ARG394, ASP351 and THR347.

Breast cancer is the most common cancer diagnosed in women and is the leading cause of death in women after cervical cancer. It is estimated in 2016 that breast cancer
accounts for 29% of all cancer cases and about 14% cause death. One of the risk factors of breast cancer is the estrogen hormone. Despite many major breakthroughs in the
field of modern medicine over the past 100 years, cancer treatment remains a significant challenge in the early 21st century. One method that can be used is virtual screening,
which is cheap, fast and reliable. Virtual screening is a complementary method in the field of medical chemistry to discover new guiding compounds. Indonesia's biodiversity is
very potential in the discovery of new compounds that are efficacious as anticancer. One of them is Piperaceae genus.

PLANTS Active representative PyMOL

SPORES
The test compound is compound is defined
drawn using BKChem and analysis is
then simulated performed to look at
docking using Testing of ChemPLP amino acid
Test compounds, PLANTS interactions in the
values includes
comparison compound bonds between the Active representative
comparisons between
(ZINC 01914469) & ligand and receptor compounds are
test compounds and
reference compound visualized into 3D
comparison compound
(ZINC 01688147) using PyMOL
or reference compound
prepared using
and one tailed paired
SPORES
T-test

BKChem R Computational Statistic

r

A B
From virtual screening result the 16-Hentriacontanone compound has the lowest
value of ChemPLP with the value of -114.7173 ± 3.3811 so this compound is
suggested for further investigation as an inhibitor against ER-α.
In Figure A the 16-Hentriacontanone compound has a structure that almost
resembles a comparative compound (ZINC 01914469) so the test compound has a
similar affinity to the ligand in the estrogen alpha receptor (ER-α). Figure B
shows the amino acids that interact in the 16-Hentriacontanone compound.
The comparation compound have very selective activity which showed in ChemPLP
value (-113.6 ± 1.4539) therefore the comparation compound is replaced by the
reference compound (ZINC 01688147).

Visualization of representatif compound with PyMOL (A) 3D overlay structure of

16-Hentriacontanone (blue) with comparison compound (pink) in protein binding 1. The compounds of the Family Piperaceae that are active as candidates for
(B) Amino acids considered to have an important role to the affinity between ER-α inhibitors are Chabamide, Dipiperamide A, Dipiperamide E,
the representative compound and ER-α are GLU353, ARG394, ASP351 and Isopiperolein B, Pipbinine, Pipercyclobutanamide A, Pipertipine, Pipgulzarine,
THR347 Pipsaeedine, Pipyahyine, Pipoxide chlorohydrins, 4,5-Dihydroxy-2-decenoic
acid piperidide, 16-Hentriacontanone, N-trans-Feruloyltyramine, Pipzorine,
Pipericine, Pipnoohine, Pipercitine, 3,4-Dimethoxy-3,4-
desmethylenecubebin, Piperolein B, Piperolein A, Piptigrine, 3,4-
Methylenedioxy-E-cinnamoyl, 3,4-Epoxypipermethystine, Cubebin, O-
Ethylcubebin, Cubebinin, Dihydroclusin, Dihydrocubebin, Hemiariensin,
1. Anita Y, Radifar M, Kardono LB, Hanafi M, Istyastono EP. Structure-based Cubebinone, Piperenol A, 5-Methoxyhinokinin, Catechol, Chavicol,
design of eugenol analogs as potential estrogen receptor antagonists. Brachystamide D, Hexacosanoic acid isobutylamide, Pipernonaline, and
Bioinformation. 2012 Oct 1;8(19):901–6. Piperundecalidine.
2. Youlden DR, Cramb SM, Yip CH, Baade PD. Incidence and mortality of female 2. Result from bonding elusidation mode of representative compounds it is
breast cancer in the Asia-Pacific region. Cancer Biol Med. 2014;11(2):101–15. indicated that the interaction with the following amino acid residues can
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screening of plants of genus Piper in breast cancer cell lines. Trop J Pharm (Glutamic Acid353), ARG394 (Arginine394), ASP351 (Aspartic Acid351) ,
Res. 2014;13(6):921–8. and THR347 (Threonine347).