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 (ER alpha) 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 ER alpha 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 ER alpha 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 ER alpha pocket (His524, Arg394 and Glu 353). However, unlike the Er alpha agonists DES and estradiol (E2), RSVL formed three additional hydrogen bonds with Gly521 and Leu525, two paramount ligand recognition residues, and with Met343 at the ER alpha binding cavity. Lastly, RSVL displayed a more favorable energy of interaction with the ER alpha binding cavity. CONCLUSIONS The present study suggests, for the first time, that RSVL is well recognized by the human ER alpha 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.