title: A molecular docking study of estrogenically active compounds with 1,2-diarylethane and 1,2-diarylethene pharmacophores.
abstract: Numerous selective estrogen receptor modulators (SERMs) have been synthesized and assayed in recent years. The focus of this study is to apply coarse-grain molecular docking procedures coupled with fine-grain all-atom force field optimization strategies to shed light on the binding mechanisms of currently available estrogen receptor-active compounds. Although the mechanics of ligand binding in estrogen receptors is generally well understood, there is room for surprises. In this paper computational evidence corroborating the experimentally observed type I agonistic binding mode for estradiol (E2) and diethylstilbesterol (DES) and the type II antagonistic binding mode for 4-hydroxytamoxifen and raloxifen is presented. Included in this type I agonistic mode are the DES derivatives, transstilbene and 1,2-diaryldiaminoethane. In addition, a novel 'type II agonistic' binding mode for 2,3-diarylimidazolines, 4,5-diarylimidazoles, 2,3-diarylpiperazines is introduced. This mode is stabilized by suggesting alternative hydrogen bond anchor points in the ligand binding domain as potential leads for future drug design.
authors.affiliation: Institut für Chemie, Freie Universität Berlin, Takustrasse 6, D14195 Berlin, Germany.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kekenes-Huskey
authors.forename: Ingo
authors.initials: I
authors.lastname: Muegge
authors.forename: Moriz
authors.initials: M
authors.lastname: von Rauch
authors.forename: Ronald
authors.initials: R
authors.lastname: Gust
authors.forename: Ernst-Walter
authors.initials: EW
authors.lastname: Knapp
mesh_terms: D003198:Computer Simulation; D004965:Estrogen Antagonists / Q000737:chemistry; D004967:Estrogens / Q000819:agonists; D004980:Ethane / Q000737:chemistry; D005030:Ethylenes / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D020845:Selective Estrogen Receptor Modulators / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D004965:Estrogen Antagonists; D004967:Estrogens; D005030:Ethylenes; D008024:Ligands; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; C036216:ethylene; D004980:Ethane