Halogenated bisphenol A derivatives potently inhibit human and rat 11β‐hydroxysteroid dehydrogenase 1: Structure–activity relationship and molecular docking

Abstract Chlorinated bisphenol A (BPA) derivatives are formed during chlorination process of drinking water, whereas bisphenol S (BPS) and brominated BPA and BPS (TBBPA and TBBPS) were synthesized for many industrial uses such as fire retardants. However, the effect of halogenated BPA and BPS derivatives on glucocorticoid metabolizing enzyme 11β‐hydroxysteroid dehydrogenase 1 (11β‐HSD1) remains unclear. The inhibitory effects of 6 BPA derivatives in the inhibition of human and rat 11β‐HSD1 were investigated. The potencies for inhibition on human 11β‐HSD1 were TBBPA (IC 50 , 3.87 μM) = monochloro BPA (MCBPA, 4.08 μM) = trichloro BPA (TrCBPA, 4.41 μM) > tetrachloro BPA (TCBPA, 9.75 μM) > TBBPS (>100 μM) = BPS (>100 μM), and those for rat 11β‐HSD1 were TrCBPA (IC 50 , 2.76 μM) = MCBPA (3.75 μM) > TBBPA (39.58 μM) > TCBPA = TBBPS = BPS. All these BPA derivatives are mixed/competitive inhibitors of both human and rat enzymes. Molecular docking studies predict that MCBPA, TrCBPA, TCBPA, and TBBPA all bind to the active site of human 11β‐HSD1, forming hydrogen bonds with catalytic residue Ser170 except TCBPA. Regression of the lowest binding energy with IC 50 values revealed a significant inverse linear regression. In conclusion, halogenated BPA derivatives are mostly potent inhibitors of human and rat 11β‐HSD1, and there is structure‐dependent inhibition.