Bisphenol A derivatives act as novel coactivator binding inhibitors for estrogen receptor β

Abstract

Bisphenol A and its derivatives are recognized endocrine disruptors based on their complex effects on estrogen receptor (ER) signaling. While the effects of bisphenol derivatives on ER have been thoroughly evaluated, how these chemicals affect ER{beta} signaling is not well understood. Herein, we identified novel ER{beta} ligands by screening a chemical library of bisphenol derivatives. Many of the compounds identified showed intriguing dual activities as ER agonists and ER{beta} antagonists. Docking simulations suggested that these compounds act as coactivator binding inhibitors (CBIs). Direct binding experiments using wild-type and mutated ER{beta} demonstrated the presence of a second ligand interaction position at the coactivator binding site in ER{beta}. Our study is the first to propose that bisphenol derivatives act as CBIs, presenting a critical view point for future ER signaling-based drug development.