title: Differential recognition of resveratrol isomers by the human estrogen receptor-alpha: molecular dynamics evidence for stereoselective ligand binding.
abstract: Resveratrol (RSVL) is a phytoestrogen that occurs naturally in two forms (trans- (E) and cis- (Z)). We have conducted molecular dynamics (MD) studies to differentially characterize the estrogen receptor-alpha (ER-alpha) binding profiles of RSVL stereoisomers. Favorable orientations for RSVL isomers at the ER-alpha pocket were first inferred from (1) alignment with pharmacophoric elements of the pure ER-alpha agonists estradiol (E2) and (2) assessment of ligand recognition by the ER-alpha binding domain. Subsequently, these orientations for RSVL isomers were subjected to MD analyses versus E2. A 100-picosecond MD simulation revealed that E2 contributed four stable hydrogen bonds with the key ER-alpha pocket residue: Arg394, Glu353, His524, and Leu525. Further, E2 displayed favorable binding energy, conformational energy change (DeltaE), and movement of the binding pocket residues (RMSd). Compared to E2, (E)-RSVL lacked a hydrogen bond (HB) with His524 but formed three additional bonds with Gly521, Phe404, and Met343 of the ER-alpha pocket. Further, (E)-RSVL conferred more favorable energy of interaction, less favorable DeltaE, but comparable RMSd values. In contrast, (Z)-RSVL orientations missed hydrogen bonding (HB) with His524 and Leu525, two essential ligand binding residues, and/or produced considerably less favorable-binding energy, -DeltaE, and -RMSd values than did (E)-RSVL. In conclusion, the present study demonstrates the utility of this MD model in distinguishing between RSVL stereoisomers. The weak binding of (Z)-RSVL by the human ER-alpha binding is congruent with its inferior ligand profiles in ER-endowed biological systems. Further, evidence is provided for a considerable variation in the mode of recognition of the mixed agonist/antagonist (E)-RSVL, and the pure agonist E2.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
authors.forename: Laila A
authors.initials: LA
authors.lastname: Abou-Zeid
authors.forename: Abdalla M
authors.initials: AM
authors.lastname: El-Mowafy
mesh_terms: D001665:Binding Sites; D047628:Estrogen Receptor alpha; D006801:Humans; D066298:In Vitro Techniques; D007529:Isoflavones / Q000737:chemistry* / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D048789:Phytoestrogens; D028321:Plant Preparations / Q000737:chemistry* / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000737:chemistry / Q000378:metabolism*; D000077185:Resveratrol; D013237:Stereoisomerism; D013267:Stilbenes / Q000737:chemistry* / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D047628:Estrogen Receptor alpha; D007529:Isoflavones; D008024:Ligands; D048789:Phytoestrogens; D028321:Plant Preparations; D011960:Receptors, Estrogen; D013267:Stilbenes; D000077185:Resveratrol