Institution: | aInstitut für Chemie, Freie Universität Berlin, Takustrasse 6, D14195 Berlin, Germany bMaterials and Process Simulation Center, California Institute of Technology, Pasadena, CA 91125, USA cBoehringer Ingelheim Pharmaceuticals, Inc., 900, Ridgebury Rd., Ridgefield, CT 06877-0368, USA dInstitut für Pharmazie, Freie Universität Berlin, Königin-Luise Str. 2-4, D14195 Berlin, Germany |
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. |