Potential activity of fevicordin-A from Phaleria macrocarpa (Scheff) Boerl. seeds as estrogen receptor antagonist based on cytotoxicity and molecular modelling studies.
Fevicordin-A (FevA) isolated from Phaleria macrocarpa (Scheff) Boerl. seeds was evaluated for its potential anticancer activity by in vitro and in silico approaches. Cytotoxicity studies indicated that FevA was selective against cell lines of human breast adenocarcinoma (MCF-7) with an IC50 value of 6.4 µM. At 11.2 µM, FevA resulted in 76.8% cell death of T-47D human breast cancer cell lines. Critical pharmacophore features amongst human Estrogen Receptor-α (hERα) antagonists were conserved in FevA with regard to a hypothesis that they could make notable contributions to its pharmacological activity. The binding stability as well as the dynamic behavior of FevA towards the hERα receptor in agonist and antagonist binding sites were probed using molecular dynamics (MD) simulation approach. Analysis of MD simulation suggested that the tail of FevA was accountable for the repulsion of the C-terminal of Helix-11 (H11) in both agonist and antagonist receptor forms. The flexibility of loop-534 indicated the ability to disrupt the hydrogen bond zipper network between H3 and H11 in hERα. In addition, MM/GBSA calculation from the molecular dynamic simulations also revealed a stronger binding affinity of FevA in antagonistic action as compared to that of agonistic action. Collectively, both the experimental and computational results indicated that FevA has potential as a candidate for an anticancer agent, which is worth promoting for further preclinical evaluation.
Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Jln. Raya Bandung Sumedang KM. 21, Jatinangor, West Java 45363, Indonesia. muchtaridi@unpad.ac.id.
Muchtaridi
M
Muchtaridi
Pharmaceutical Design and Simulation Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Penang, Pulau Pinang, Malaysia. myusuf_setiabudi@yahoo.com.
Muhammad
M
Yusuf
Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Jln. Raya Bandung Sumedang KM. 21, Jatinangor, West Java 45363, Indonesia. ajengdradjad@yahoo.com.
Ajeng
A
Diantini
Pharmaceutical Design and Simulation Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Penang, Pulau Pinang, Malaysia. sybing@gmail.com.
Sy Bing
SB
Choi
Pharmaceutical Design and Simulation Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Penang, Pulau Pinang, Malaysia. najjar.belal@gmail.com.
Belal O
BO
Al-Najjar
Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Jln. Raya Bandung Sumedang KM. 21, Jatinangor, West Java 45363, Indonesia. freemanusia@yahoo.com.
Jerry V
JV
Manurung
Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Jln. Raya Bandung Sumedang KM. 21, Jatinangor, West Java 45363, Indonesia. aasubarnas@yahoo.co.id.
Anas
A
Subarnas
Faculty of Medicine, Universitas Padjadjaran, Jln. Raya Bandung-Sumedang KM. 21, Jatinangor, West Java 45363, Indonesia. tachmad@fk.unpad.ac.id.
Tri H
TH
Achmad
Faculty of Medicine, Universitas Padjadjaran, Jln. Raya Bandung-Sumedang KM. 21, Jatinangor, West Java 45363, Indonesia. wsavitrirestu@yahoo.com.
Savitri R
SR
Wardhani
Pharmaceutical Design and Simulation Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Penang, Pulau Pinang, Malaysia. habibah@ipharm.gov.my.
Habibah A
HA
Wahab
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D054728:Cucurbitacins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D065171:Estrogen Receptor Antagonists / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D012639:Seeds / Q000737:chemistry; D013816:Thermodynamics; D029645:Thymelaeaceae / Q000737:chemistry*
D000972:Antineoplastic Agents, Phytogenic; C506487:ESR1 protein, human; D065171:Estrogen Receptor Antagonists; D047628:Estrogen Receptor alpha; C000594529:fevicordin-A; D054728:Cucurbitacins