Discovery of novel oestrogen receptor \u03b1 agonists and antagonists by screening a revisited privileged structure moiety for nuclear receptors

Takahiro Masuya,Masaki Iwamoto,Xiaohui Liu,Ayami Matsushima

doi:10.1038/s41598-019-46272-y

Takahiro Masuya, Masaki Iwamoto + Show 2 more

Open Access

https://doi.org/10.1038/s41598-019-46272-y

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Journal: Scientific Reports	Publication Date: Jul 9, 2019
Citations: 13	License type: open-access

Affiliation: Kyushu University

Abstract

Bisphenol A (BPA) is used as an industrial raw material for polycarbonate plastics and epoxy resins; however, various concerns have been reported regarding its status as an endocrine-disrupting chemical. BPA interacts not only with oestrogen receptors (ERs) but constitutive androstane receptor, pregnane X receptor, and oestrogen-related receptor γ (ERRγ); therefore, the bisphenol structure represents a privileged structure for the nuclear-receptor superfamily. Here, we screen 127 BPA-related compounds by competitive-binding assay using [3H]oestradiol and find that 20 compounds bind to ERα with high affinity. We confirm most of these as ERα agonists; however, four compounds, including bisphenol M and bisphenol P act as novel antagonists. These structures harbour three benzene rings in tandem with terminal hydroxy groups at para-positions, with this tandem tri-ring bisphenol structure representing a novel privileged structure for an ERα antagonist. Additionally, we perform an ab initio calculation and develop a new clipping method for halogen bonding or non-covalent interaction using DV-Xα evaluation for biomolecules.

Highlights

Bisphenol A [BPA; HO-C6H4-C(CH3CH3)-C6H5-OH] is a chemical used in the production of polycarbonate plastics and epoxy resins; maternal exposure to BPA is considered a developmental and behavioural risk later in life in humans and model animals
[3H]E2 against ERα to evaluate 127 commercially available bisphenol or benzylphenol derivatives, some of which are used as industrial raw materials for polycarbonate plastics
We found that 70 compounds (>55% of the compounds tested) bound to the ligand-binding domain (LBD) of ERα responsible for ligand-dependent activation function

Summary

Introduction

Bisphenol A [BPA; HO-C6H4-C(CH3CH3)-C6H5-OH] is a chemical used in the production of polycarbonate plastics and epoxy resins; maternal exposure to BPA is considered a developmental and behavioural risk later in life in humans and model animals. The crystal structure of the BPA–ERRγ complex is the first of an EDC-bound nuclear receptor and shows multiple intermolecular interactions via benzene rings that promote BPA binding in the ligand-binding pocket of ERRγ21. These findings imply that bisphenol and/or benzylphenol structures represent privileged structures for the nuclear-receptor superfamily, with this concept first introduced in 1988 and still recognized as a useful definition for drug-target leads in the field of medicinal chemistry[22,23]. The aim of this study is to confirm that bisphenol and/or benzylphenol structures are privileged structures for ERα binding and demonstrate the efficacy of our method for assessing utility of halogen bonds to promote ligand binding

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