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

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 recep...

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Autores principales:	Takahiro Masuya, Masaki Iwamoto, Xiaohui Liu, Ayami Matsushima
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/956596e20f744559b0aa97cd1bc89037
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spelling	oai:doaj.org-article:956596e20f744559b0aa97cd1bc890372021-12-02T15:09:46ZDiscovery of novel oestrogen receptor α agonists and antagonists by screening a revisited privileged structure moiety for nuclear receptors10.1038/s41598-019-46272-y2045-2322https://doaj.org/article/956596e20f744559b0aa97cd1bc890372019-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-46272-yhttps://doaj.org/toc/2045-2322Abstract 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.Takahiro MasuyaMasaki IwamotoXiaohui LiuAyami MatsushimaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-11 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Takahiro Masuya Masaki Iwamoto Xiaohui Liu Ayami Matsushima Discovery of novel oestrogen receptor α agonists and antagonists by screening a revisited privileged structure moiety for nuclear receptors
description	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.
format	article
author	Takahiro Masuya Masaki Iwamoto Xiaohui Liu Ayami Matsushima
author_facet	Takahiro Masuya Masaki Iwamoto Xiaohui Liu Ayami Matsushima
author_sort	Takahiro Masuya
title	Discovery of novel oestrogen receptor α agonists and antagonists by screening a revisited privileged structure moiety for nuclear receptors
title_short	Discovery of novel oestrogen receptor α agonists and antagonists by screening a revisited privileged structure moiety for nuclear receptors
title_full	Discovery of novel oestrogen receptor α agonists and antagonists by screening a revisited privileged structure moiety for nuclear receptors
title_fullStr	Discovery of novel oestrogen receptor α agonists and antagonists by screening a revisited privileged structure moiety for nuclear receptors
title_full_unstemmed	Discovery of novel oestrogen receptor α agonists and antagonists by screening a revisited privileged structure moiety for nuclear receptors
title_sort	discovery of novel oestrogen receptor α agonists and antagonists by screening a revisited privileged structure moiety for nuclear receptors
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/956596e20f744559b0aa97cd1bc89037
work_keys_str_mv	AT takahiromasuya discoveryofnoveloestrogenreceptoraagonistsandantagonistsbyscreeningarevisitedprivilegedstructuremoietyfornuclearreceptors AT masakiiwamoto discoveryofnoveloestrogenreceptoraagonistsandantagonistsbyscreeningarevisitedprivilegedstructuremoietyfornuclearreceptors AT xiaohuiliu discoveryofnoveloestrogenreceptoraagonistsandantagonistsbyscreeningarevisitedprivilegedstructuremoietyfornuclearreceptors AT ayamimatsushima discoveryofnoveloestrogenreceptoraagonistsandantagonistsbyscreeningarevisitedprivilegedstructuremoietyfornuclearreceptors
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Discovery of novel oestrogen receptor α agonists and antagonists by screening a revisited privileged structure moiety for nuclear receptors

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