THE ESTRADIOL PHARMACOPHORE - LIGAND STRUCTURE-ESTROGEN RECEPTOR-BINDING AFFINITY RELATIONSHIPS AND A MODEL FOR THE RECEPTOR-BINDING SITE

The accumulated knowledge on the binding of estradiol (E(2)) and its a nalogs and the results of affinity-labeling studies have been reviewed and are used herein to derive a binding site model for the estrogen r eceptor (ER). Estradiol is nonpolar and hydrophobic, except at its mol ecular termini. Most of its skeletal flexibility resides in the B-ring , and it probably binds in a low-energy conformation. The phenolic OH group in the A-ring contributes about 1.9 kcal/mol to the binding free energy and probably acts primarily as a hydrogen bond donor. The 17 b eta-hydroxyl group in the D-ring contributes approximately 0.6 kcal/mo l to the binding and probably acts as a hydrogen bond acceptor, either directly or via a water molecule. There also seems to be a degree of flexibility in the region of the receptor that encompasses the D-ring. The aromatic ring contributes about 1.5 kcal/mol, probably through we ak polar interactions with receptor residues that contact the beta-fac e of the steroid. The receptor seems to surround the ligand, so that a ll four rings contribute significantly to binding. Small hydrophobic s ubstituents enhance binding affinity at positions 4, 12 beta, 14, and 16 alpha; whereas, larger hydrophobic substituents are tolerated at po sitions 7 alpha, 11 beta, and 17 alpha. In general, the ER is intolera nt of polar substituents. Based on E(2) analogs bearing affinity-label ing groups, cysteine residues might be present in the binding site in the area of C-4, C-17 alpha, and C-17 beta, and a lysine residue might be located near C-16. Models that represent the limits of deformabili ty of the ligand binding site, the position of preformed pockets, and space occupied by the receptor are presented. The various elements in this model for the binding of steroidal estrogens by the estrogen rece ptor are consistent with evidence emerging from the crystal structures of related nuclear hormone receptor ligand complexes. (C) 1997 by Els evier Science Inc.