Distinct inhibitory strength of bisphenol A analogues on human and rat 11p-hydroxysteroid dehydrogenase 1: 3D quantitative structure-activity relationship and in silico molecular docking analysis

Bisphenol A (BPA) analogues are developed to replace BPA usage. However, their effects on 11 beta-hydroxysteroid dehydrogenase 1 (11 beta-HSD1) are largely unknown. The inhibitory effects of BPA and 10 BPA analogues with the substituents on the bridge moiety on human and rat 11 beta-HSD1 were explored in human and rat liver microsomes. The strength of inhibiting human 11 beta-HSD1 was bisphenol FL (IC50, 3.87 mu M) > bisphenol Z (6.86 mu M) > bisphenol AF (9.42 mu M) > bisphenol C (16.14 mu M) > bisphenol AP (32.14 mu M) = bisphenol B (32.34 mu M) > 4,4'-thiodiphenol (67.35 mu M) > BPA (297.35 mu M) > other BPA analogues (ineffective at 100 mu M). The strength of inhibiting rat 11 beta-HSD1 was bisphenol Z (IC50, 14.44 mu M) > 4,4'-thiodiphenol (19.01 mu M) > bisphenol B (20.13 mu M) > bisphenol F (22.10 mu M) > bisphenol E (33.04 mu M) > bisphenol AF (49.67 mu M) > bisphenol C > (56.97 mu M) > bisphenol AP (62.71 mu M) >bisphenol FL (96.31 mu M) > other BPA analogues (ineffective at 100 mu M). Bisphenol A, AF, AP, B, C, F, FL, Z, and 4,4'-thiodiphenol bind to the active sites of human and rat 11 beta-HSD1. Regression of LogP and molecular weight with IC50 values revealed distinct inhibitory pattern (negative correlation for human 11 beta-HSD1 vs. positive correlation for rat enzyme). Regression of the lowest binding energy with IC50 values revealed a significant positive regression. 3D QSAR pharmacophore analysis showed one hydrogen bond acceptor and two hydrogen bond donors for human 11 beta-HSD1. In conclusion, most BPA analogues are more potent inhibitors of human and rat 11 beta-HSD1 enzymes and there is structure-dependent and species-dependent inhibition.