Computer-Aided Drug Design Unveils the Structural Requisites for Bile Acid Receptors Modulation

Bile acids (BAs) largely control lipids and glucose metabolism interacting with nuclear and cell membrane receptors. Among these, the G-protein coupled bile acid receptor 1 (GPBAR1) is now considered a major target for the treatment of several enterohepatic and metabolic disorders, including type 2 diabetes mellitus (T2DM). Over the last decade, the design of specific GPBAR1 ligands has been hampered by the lack of an experimental structure of hGPBAR1. To overcome this limitation, we have used homology modeling to build the tridimensional structure of this receptor. Then, we have investigated the binding mode of some potent bile acid derivatives to the GPBAR1 model by combining molecular docking studies with extensive molecular dynamics (MD) simulations in explicit membrane. These studies have allowed elucidating the structural requirements not only for GPBAR1 recognition by bile acid derivatives but also for achieving selectivity over other bile acid receptors like the nuclear farnesoid X receptor (FXR). In particular, we found that: i) the stereochemistry of rings A and B as well as the BAs side chain length can deeply influence the affinity towards GPBAR1 and FXR; ii) the nature and the stereochemistry of the small polar groups at C3 and C7 positions on the BA scaffold are critical to modulate GPBAR1 affinity and GPBAR1/FXR selectivity; iii) the insertion of an additional alkyl substituent at C6 position greatly increases the potency towards both receptors. These outcomes have provided fundamental insights into bile acid receptors activity regulation, paving the way for the rational design of a new generation of potent and selective drug-like GPBAR1 modulators.