Molecular Initiating Events of Bisphenols on Androgen Receptor-Mediated Pathways Provide Guidelines for in Silico Screening and Design of Substitute Compounds

Bisphenols (BPs) have the potential to interfere with the androgen receptor (AR). However, in silico screening and substitute design were difficult because little was known about the mechanisms by which BPs interfere with AR-mediated molecular initiating events (MIEs). Here, the AR disrupting effects and associated mechanisms of 15 BPs were evaluated by in vitro assays and molecular dynamics simulations. AR-mediated MIEs, including ligand-receptor interactions and coregulator recruitment, might determine active versus inactive and agonist versus antagonist activities of BPs, respectively. Bisphenol E (BPE), BPF, and BPS with no binding effects were inactive, while all other BPs were AR antagonists. On the basis of their coregulator recruitment patterns and repositioning of helix 12, BPBP, BPC, and BPPH were passive antagonists that blocked coregulator recruitment, and their anti-androgenic potencies were correlated with ligand-receptor interactions; others were active antagonists that recruited corepressors, and their anti-androgenic potencies were correlated with ligand-receptor-corepressor interactions. A new method was developed for MIE-based in silico qualitative and quantitative evaluations of the potential of BPs to disrupt AR-mediated pathways, by which safer BPA substitutes with smaller and less hydrophobic connecting groups could be designed. The MIE-based in silico methods can be used to screen a wider range of chemicals and to design better substitutes.