Differential recognition of resveratrol isomers by the human estrogen receptor-α:: Molecular dynamics evidence for stereoselective ligand binding

被引:23
作者
Abou-Zeid, LA
El-Mowafy, AM
机构
[1] Univ Mansoura, Fac Pharm, Dept Med Chem, Mansoura, Egypt
[2] Masoura Univ, Fac Pharm, Dept Biochem Pharmacol, Mansoura, Egypt
关键词
resveratrol; (E) and (Z) isomers; estrogen receptor; molecular dynamics;
D O I
10.1002/chir.20007
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 agonist 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 domain 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. Chirality 16:190-195, 2004. (C) 2004Wiley-Liss, Inc.
引用
收藏
页码:190 / 195
页数:6
相关论文
共 32 条
  • [1] Molecular dynamics simulation characteristics of resveratrol interaction with human estrogen receptor-α:: distinct recognition from diethylstilbestrol
    Abou-Zeid, LA
    El-Mowafy, AM
    [J]. JOURNAL OF MOLECULAR STRUCTURE-THEOCHEM, 2002, 593 : 39 - 48
  • [2] [Anonymous], 1999, HYP MOL MOD SYST REL
  • [3] The estradiol pharmacophore: Ligand structure-estrogen receptor binding affinity relationships and a model for the receptor binding site
    Anstead, GM
    Carlson, KE
    Katzenellenbogen, JA
    [J]. STEROIDS, 1997, 62 (03) : 268 - 303
  • [4] Estrogenic/antiestrogenic and scavenging properties of (E)- and (Z)-resveratrol
    Basly, JP
    Marre-Fournier, F
    Le Bail, JC
    Habrioux, G
    Chulia, AJ
    [J]. LIFE SCIENCES, 2000, 66 (09) : 769 - 777
  • [5] Bertelli AAE, 1996, DRUG EXP CLIN RES, V22, P61
  • [6] BERTELLI AAE, 1995, INT J TISSUE REACT, V17, P1
  • [7] Resveratrol acts as a mixed agonist/antagonist for estrogen receptors α and β
    Bowers, JL
    Tyulmenkov, VV
    Jernigan, SC
    Klinge, CM
    [J]. ENDOCRINOLOGY, 2000, 141 (10) : 3657 - 3667
  • [8] Molecular basis of agonism and antagonism in the oestrogen receptor
    Brzozowski, AM
    Pike, ACW
    Dauter, Z
    Hubbard, RE
    Bonn, T
    Engstrom, O
    Ohman, L
    Greene, GL
    Gustafsson, JA
    Carlquist, M
    [J]. NATURE, 1997, 389 (6652) : 753 - 758
  • [9] DAVID T, 1998, P NATL SCI US, V95, P5998
  • [10] Different residues of the human estrogen receptor are involved in the recognition of structurally diverse estrogens and antiestrogens
    Ekena, K
    Weis, KE
    Katzenellenbogen, JA
    Katzenellenbogen, BS
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (08) : 5069 - 5075