Bisphenol analogues inhibit human and rat 17β-hydroxysteroid dehydrogenase 1: 3D-quantitative structure-activity relationship (3D-QSAR) and in silico docking analysis

Sailing Chen; Shaowei Wang; Jingyi Zheng; Han Lu; Huiqian Chen; Yunbing Tang; Nan Wang; Yang Zhu; Yiyan Wang; Ping Duan; Ren-Shan Ge

doi:10.1016/j.fct.2023.114052

Bisphenol analogues inhibit human and rat 17β-hydroxysteroid dehydrogenase 1: 3D-quantitative structure-activity relationship (3D-QSAR) and in silico docking analysis

Food Chem Toxicol. 2023 Nov:181:114052. doi: 10.1016/j.fct.2023.114052. Epub 2023 Sep 26.

Authors

Sailing Chen¹, Shaowei Wang¹, Jingyi Zheng², Han Lu¹, Huiqian Chen¹, Yunbing Tang¹, Nan Wang¹, Yang Zhu², Yiyan Wang², Ping Duan³, Ren-Shan Ge⁴

Affiliations

¹ Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China.
² Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital, Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China.
³ Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China. Electronic address: dppddpp@wmu.edu.cn.
⁴ Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China; Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital, Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China; Key Laboratory of Structural Malformations in Children of Zhejiang Province and Key Laboratory of Male Health and Environment of Wenzhou, 325000, Zhejiang Province, China. Electronic address: renshan_ge@wmu.edu.cn.

PMID: 37758047
DOI: 10.1016/j.fct.2023.114052

Abstract

Bisphenols, estrogenic endocrine-disrupting chemicals, disrupt at least one of three endocrine pathways (estrogen, androgen, and thyroid). 17β-Hydroxysteroid dehydrogenase 1 (17β-HSD1) is a steroidogenic enzyme that catalyzes the activation of estradiol from estrone in human placenta and rat ovary. However, whether bisphenols inhibit 17β-HSD1 and the mode of action remains unclear. This study we screened 17 bisphenols for inhibiting human 17β-HSD1 in placental microsomes and rat 17β-HSD1 in ovarian microsomes and determined 3D-quantitative structure-activity relationship (3D-QSAR) and mode of action. We observed some bisphenols with substituents were found to significantly inhibit both human and rat 17β-HSD1 with the most potent inhibition on human enzyme by bisphenol H (IC₅₀ = 0.90 μM) when compared to bisphenol A (IC₅₀ = 113.38 μM). Rat enzyme was less sensitive to the inhibition of bisphenols than human enzyme with bisphenol H (IC₅₀ = 32.94 μM) for rat enzyme. We observed an inverse correlation between IC₅₀ and hydrophobicity (expressed as Log P). Docking analysis showed that they bound steroid-binding site of 17β-HSD1. The 3D-QSAR models demonstrated that hydrophobic region, hydrophobic aromatic, ring aromatic, and hydrogen bond acceptor are key factors for the inhibition of steroid synthesis activity of 17β-HSD1.

Keywords: 17β-HSD1; 3D-QSAR; Autodock; Bisphenols; Steroidogenesis.

MeSH terms

Animals
Enzyme Inhibitors* / pharmacology
Estrone / chemistry
Estrone / pharmacology
Female
Humans
Models, Molecular
Placenta
Pregnancy
Quantitative Structure-Activity Relationship*
Rats
Structure-Activity Relationship

Substances

3 (or 17)-beta-hydroxysteroid dehydrogenase
bisphenol A
Enzyme Inhibitors
Estrone