Estrogenic properties of coumarins and meroterpene from the fruits of Cullen corylifolium: Experimental and computational studies

摘要

Coumarins and meroterpene from the fruits of Cullen corylifolium were evaluated for their ability to bind and activate human estrogen receptor alpha (hER alpha) by a combination of in vitro studies and molecular dynamics simulations. The recombinant hER alpha ligand binding domain (hER alpha-LBD) was produced in BL21 (DE3)pLysS and the fluorescence polarization (FP) assay was performed to determine the binding affinities of coumarins and meroterpene with receptor protein. These compounds displayed distinct binding potency toward hER alpha-LBD, generally increased with their increasing molecular length and Connolly solvent-excluded volume (CSEV). In an estrogen response element-luciferase (ERE-Luc) reporter gene assay, coumarins and meroterpene acted as agonists of human estrogen receptor alpha. Subsequently, molecular docking was conducted to elucidate the molecular mechanism behind their agonistic activities. Coumarins and meroterpene adopted an agonist conformation within the cavity of hER alpha-LBD. The hydrophobic and hydrogen-bonding interactions were dominant forces to stabilize their binding. The structure-activity relationship analysis suggested that the presence of hydroxyl groups and prenyl group were crucial for possessing estrogenic activities. Comparison of the calculated binding energies with the determined binding affinities yielded a good correlation (R-2 = 0.9727). In conclusion, molecular modeling techniques can potentially be applied for in silico screening of selective estrogen receptor modulators (SERMs) from undescribed compounds.