I. The Development of Estrogen Receptor Coactivator Binding Inhibitors. II. Investigations Into the Binding Modes of Ligands Selective for Estrogen Receptor Alpha

Abstract

Our laboratory has previously discovered that certain heterocycles show high binding affinity and selectivity for ERalpha. In order to design more potent and selective derivatives, a better understanding of how they bind to the receptor is needed. Using a comparative binding analysis method and molecular modeling, we were able to assess the binding mode of a furan agonist and antagonist. As an agonist, the furan binds to the receptor with the C(2) phenol acting as the A-ring in most cases. As an antagonist, the furan binds with the C(5) phenol acting as the A-ring mimic and the basic side chain extending back into the pocket in a similar fashion to known antagonists. The preparation of various mono and bisphenolic furan analogs in conjunction with molecular modeling assisted in confirming these assertions.