Differential Targeting of Peroxisome Proliferator-Activated Receptor-α by Bisphenol A and its Halogenated Analogues: An In Silico Study

Widespread exposure to bisphenol A (BPA) is suspected to affect a variety of physiological functions. There is accumulating evidence showing the role of BPA as an endocrine disrupting chemical mainly due to its estrogenic activity. Although BPA has been substituted by its analogues, effects of BPA and its analogues on metabolic pathways have been poorly investigated. Additionally, BPA has been also shown to bind and activate other receptors including peroxisome proliferator-activated receptors (PPARs). PPARs act as transcription factors by regulating genes involved in adipogenesis, and glucose, lipid, and cholesterol metabolism. An in silico study looking into the binding efficiency of BPA and its halogenated analogues with PPARα of mouse was undertaken. The idea was to understand the mechanism of interaction of bisphenols with PPARα. In the absence of a crystal structure for mouse PPARs, homology modelling was performed to generate the crystal structure of PPARα using Modeller 9 v10. The desired protein template was identified through BLASTp search against the protein database. For docking studies, grid boxes were created at the hinge of PPARα and each ligand was individually docked using the AutoDock-4.2. Docking analysis was done by PyMOL and results prepared on Chimara v1.8. Upon interaction with mouse PPARα BPA and its halogenated analogues showed lowest binding energy scores (Kcal/Mol) were in the order: TBBPA (-8.75) ˃BPZ (-8.09) ˃ BPC = TCBPA (-7.77) ˃ BPE (-7.24) ˃ BPB (-7.15) ˃ BPF (7.02) ˃ BPS (6.02) ˃ BPA (5.60) ˃ BPAF (-5.39). Lowest binding energy score of positive control GW 7647 was -7.89. Certain BPA analogues showed higher binding efficiency with PPARα than BPA. Overall, the results suggest that some of the halogenated analogues of BPA have strong binding affinity. Further in vivo and in vitro studies are required for determining their actual safety profiling.