Potential Activity of Fevicordin-A from Phaleria macrocarpa (Scheff) Boerl. Seeds as Estrogen Receptor Antagonist Based on Cytotoxicity and Molecular Modelling Studies
Open Access
- 25 April 2014
- journal article
- research article
- Published by MDPI AG in International Journal of Molecular Sciences
- Vol. 15 (5), 7225-7249
- https://doi.org/10.3390/ijms15057225
Abstract
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.This publication has 55 references indexed in Scilit:
- The Role of Early-Life Socioeconomic Status in Breast Cancer Incidence and MortalityJournal of Aging and Health, 2011
- Early-Life Socioeconomic Status and the Prevalence of Breast Cancer in Later LifeResearch on Aging, 2011
- The 2010 Philip S. Portoghese Medicinal Chemistry Lectureship: Addressing the “Core Issue” in the Design of Estrogen Receptor LigandsJournal of Medicinal Chemistry, 2011
- Characterization of the Pharmacophore Properties of Novel Selective Estrogen Receptor Downregulators (SERDs)Journal of Medicinal Chemistry, 2010
- Structural plasticity in the oestrogen receptor ligand‐binding domainEMBO Reports, 2007
- The role of estrogen in the initiation of breast cancerThe Journal of Steroid Biochemistry and Molecular Biology, 2006
- Estrogens and their receptors in breast cancer progression: a dual role in cancer proliferation and invasionCritical Reviews in Oncology/Hematology, 2004
- Development and testing of a general amber force fieldJournal of Computational Chemistry, 2004
- A point‐charge force field for molecular mechanics simulations of proteins based on condensed‐phase quantum mechanical calculationsJournal of Computational Chemistry, 2003
- CHARMM: A program for macromolecular energy, minimization, and dynamics calculationsJournal of Computational Chemistry, 1983