Recognition of resveratrol by the human estrogen receptor-alpha: A molecular modeling approach to understand its biological actions

Objectives: Resveratrol (RSVL) is an edible phytoestrogen with multifaceted health benefits that may originate from binding to the estrogen receptors. Despite its structural similarity to the estrogen receptor-alpha (ERalpha) agonist diethylstilbestrol (DES), RSVL showed distinct biological profiles in estrogen-responsive biological systems. The molecular basis of such biological profiles has been undefined, Methods: We considered possible orientations for RSVL in ERalpha binding pocket. These conformations have been analyzed based on: (i) alignment with the key pharmacophoric elements of DES; (ii) computational energy of interaction, and (iii) pattern of accommodation at the ERa binding pocket. The characteristics of the most favored RSVL orientation have been compared with those of DES. Results: Both RSVL and DES interacted with the catalytic amino acid triad of the ERa pocket (His524, Arg394 and Glu 353). However, unlike the Era agonists DES and estradiol (E-2), RSVL formed three additional hydrogen bonds with Gly521 and Leu525, two paramount ligand recognition residues, and with Met343 at the ERalpha binding cavity. Lastly, RSVL displayed a more favorable energy of interaction with the ERa binding cavity. Conclusions:The present study suggests, for the first time, that RSVL is well recognized by the human ERalpha but in a manner distinct from the pure agonists DES and E2(.) These variations may well entail the unique biological responses of RSVL in ER-responsive systems. Copyright (C) 2002 S. Karger AG, Basel.