Bile Acids Are Potential Negative Allosteric Modulators of M1 Muscarinic Receptors.

The proposed physiological roles of bile acids have expanded beyond the digestion of fats to encompass cell signaling via the activation of a variety of nuclear and plasma membrane receptors in multiple organ systems. The current in silico study was inspired by previous observations from our group and others that bile acids interact functionally with cardiac, pulmonary, and gastrointestinal muscarinic receptors and more recent work demonstrating allosteric binding of cholesterol, the parent molecule for bile acid synthesis, to M muscarinic receptors (MR). Here, we computationally tested the hypothesis that bile acids can allosterically bind to MR and thereby modulate receptor activation. Utilizing de novo site identification by the ligand competitive saturation (SILCS) method, putative novel allosteric binding sites of bile acid targeting MR were identified. Molecular dynamics simulations were used to uncover the molecular details of the activation mechanism of MR due to agonist binding along with allosteric modulation of bile acids on MR activation. Allosteric binding of bile acids and their glycine and taurine conjugates to MR negatively impacts the activation process, findings consistent with recent reports that MR expression and activation inhibit colon cancer cell proliferation. Thus, bile acids may augment colon cancer risk by inhibiting the tumor suppressor actions of MR. When validated experimentally, these findings are anticipated to shed light on our understanding of how bile acids in the membrane microenvironment can allosterically modulate the function of MR and possibly other G protein-coupled receptors.