Importance of Receptor Conformations in Docking Calculation-Based Risk Assessment for Endocrine Disruptors against Estrogen Receptor α

Hitoshi Kesamaru, Keitaro Suyama, Takeru Nose

研究成果: ジャーナルへの寄稿記事

抄録

Employment of appropriate receptor conformations as templates is essential for appropriate identification of the latent receptor binding ability of chemicals using in silico docking calculations. In this study, we performed docking calculations using a number of agonist- and antagonist-bound conformations of 83 estrogen receptor (ER) α-ligand-binding domains as templates to clarify the type of receptor conformations required for reasonable identification of endocrine disruptors. Our results showed that 17β-estradiol and diethylstilbestrol (ERα agonists) bound preferentially to the agonist conformations, whereas 4-hydroxytamoxifen and raloxifene (ERα antagonists) bound selectively to the antagonist conformations. We also observed that bisphenol A analogues, which are partial agonists, bound more moderately and preferentially to the agonist conformations as compared with the antagonist conformations. Additionally, the docking calculations were able to estimate biological agonist or antagonist activity of chemicals based on the receptor conformation selectivity. Furthermore, structural analyses of the ligand-binding domains and docking calculation utilizing C-terminal-truncated receptors indicated that the C-terminal regions of these domains were capable of discriminating agonists from nonagonists. These results suggest that both agonist- and antagonist-binding conformations of receptors are necessary to predict the binding affinity and biological activity of chemicals for docking calculation-based risk assessment. Furthermore, this in silico method can be beneficial for drug discovery because it is useful for rapid searching of ligands for receptors and preventing the side effects caused by unfavorable receptor binding.

元の言語英語
ページ(範囲)6620-6629
ページ数10
ジャーナルACS Omega
4
発行部数4
DOI
出版物ステータス出版済み - 4 10 2019

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Endocrine Disruptors
Estrogen Receptors
Risk assessment
Conformations
Ligands
Estrogens
Diethylstilbestrol
Bioactivity
Estradiol

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Chemical Engineering(all)

これを引用

Importance of Receptor Conformations in Docking Calculation-Based Risk Assessment for Endocrine Disruptors against Estrogen Receptor α. / Kesamaru, Hitoshi; Suyama, Keitaro; Nose, Takeru.

:: ACS Omega, 巻 4, 番号 4, 10.04.2019, p. 6620-6629.

研究成果: ジャーナルへの寄稿記事

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