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Int. J. Mol. Sci. 2014, 15(5), 7225-7249; doi:10.3390/ijms15057225

Potential Activity of Fevicordin-A from Phaleria macrocarpa (Scheff) Boerl. Seeds as Estrogen Receptor Antagonist Based on Cytotoxicity and Molecular Modelling Studies

Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Jln. Raya Bandung Sumedang KM. 21, Jatinangor, West Java 45363, Indonesia
Pharmaceutical Design and Simulation Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Penang, Pulau Pinang, Malaysia
Faculty of Medicine, Universitas Padjadjaran, Jln. Raya Bandung-Sumedang KM. 21, Jatinangor, West Java 45363, Indonesia
Malaysian Institute of Pharmaceuticals and Nutraceuticals, Ministry of Science, Technology and Innovation, Halaman Bukit Gambir, 11700 Penang, Pulau Pinang, Malaysia
These authors contributed equally to this work.
Authors to whom correspondence should be addressed.
Received: 22 November 2013 / Revised: 10 January 2014 / Accepted: 15 January 2014 / Published: 25 April 2014
(This article belongs to the Collection Proteins and Protein-Ligand Interactions)
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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. View Full-Text
Keywords: fevicordin A; estrogen receptor; pharmacophore; molecular dynamics; Phaleria macrocarpa fevicordin A; estrogen receptor; pharmacophore; molecular dynamics; Phaleria macrocarpa

This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Muchtaridi, M.; Yusuf, M.; Diantini, A.; Choi, S.B.; Al-Najjar, B.O.; Manurung, J.V.; Subarnas, A.; Achmad, T.H.; Wardhani, S.R.; Wahab, H.A. Potential Activity of Fevicordin-A from Phaleria macrocarpa (Scheff) Boerl. Seeds as Estrogen Receptor Antagonist Based on Cytotoxicity and Molecular Modelling Studies. Int. J. Mol. Sci. 2014, 15, 7225-7249.

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