Proanthocyanidin B2 derived metabolites may be ligands for bile acid receptors S1PR2, PXR and CAR: an in silico approach

Bile acids (BAs) act as signaling molecules via their interactions with various nuclear (FXR, VDR, PXR and CAR) and G-protein coupled (TGR5, M3R, S1PR2) BA receptors. Stimulation of these BA receptors influences several processes, including inflammatory responses and glucose and xenobiotic metabolism. BA profiles and BA receptor activity are deregulated in cardiometabolic diseases; however, dietary polyphenols were shown to alter BA profile and signaling in association with improved metabolic phenotypes. We previously reported that supplementing mice with a proanthocyanidin (PAC)-rich grape polyphenol (GP) extract attenuated symptoms of glucose intolerance in association with changes to BA profiles, BA receptor gene expression, and/or downstream markers of BA receptor activity. Exact mechanisms by which polyphenols modulate BA signaling are not known, but some hypotheses include modulation of the BA profile via changes to gut bacteria, or alteration of ligand-availability via BA sequestration. Herein, we used an in silico approach to investigate putative binding affinities of proanthocyanidin B2 (PACB2) and PACB2 metabolites to nuclear and G-protein coupled BA receptors. Molecular docking and dynamics simulations revealed that certain PACB2 metabolites had stable binding affinities to S1PR2, PXR and CAR, comparable to that of known natural and synthetic BA ligands. These findings suggest PACB2 metabolites may be novel ligands of S1PR2, CAR, and PXR receptors. Communicated by Ramaswamy H. Sarma