Please cite this article as: RRH: Dual role of bisphenols as ERα-agonists and ERβ-antagonists This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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 ERα have been thoroughly evaluated, how these chemicals affect ERβ signaling is not well understood. Herein, we identified novel ERβ ligands by screening a chemical library of bisphenol derivatives. Many of the compounds identified showed intriguing dual activities as ERα agonists and ERβ antagonists. Docking simulations suggested that these compounds act as coactivator binding inhibitors (CBIs). Direct binding experiments using wild-type and mutated ERβ demonstrated the presence of a second ligand interaction position at the coactivator binding site in ERβ. 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.
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