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

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 (IC 50  = 0.90 μM) when compared to bisphenol A (IC 50  = 113.38 μM). Rat enzyme was less sensitive to the inhibition of bisphenols than human enzyme with bisphenol H (IC 50  = 32.94 μM) for rat enzyme. We observed an inverse correlation between IC 50 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.