TY - JOUR
T1 - Discovery of novel oestrogen receptor α agonists and antagonists by screening a revisited privileged structure moiety for nuclear receptors
AU - Masuya, Takahiro
AU - Iwamoto, Masaki
AU - Liu, Xiaohui
AU - Matsushima, Ayami
N1 - Funding Information:
The authors would like to thank K.B. Sharpless (The Scripps Research Institute) for discussions concerning this work and Y. Shimohigashi (Kyushu University) for providing the chemical library. This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI [Grant Nos JP17H01881 and JP18K19147 to A.M.], in part by the scholar project of The Toyota Physical and Chemical Research Institute, and a research grant from the Kato Memorial Bioscience Foundation.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85068766775&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85068766775&partnerID=8YFLogxK
U2 - 10.1038/s41598-019-46272-y
DO - 10.1038/s41598-019-46272-y
M3 - Article
C2 - 31289329
AN - SCOPUS:85068766775
VL - 9
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 9954
ER -