Identification of new non-steroidal TGR5 agonists using virtual screening with combined pharmacophore models

Activation of Takeda G-protein receptor 5 (TGR5) plays a key role in pathways associated with diabetes, metabolic syndrome, and autoimmune disease. Pharmacophore and 3D-quantitative structure-activity relationship modeling were applied to study the structure-activity relationship of TGR5 agonists. The best HypoGen pharmacophore hypothesis Hypo1 with a correlation coefficient of 0.93 consists of one hydrogen-bond acceptor, one aromatic ring and three hydrophobic features, whereas the best phase hypothesis AHHRR.1321 with favorable statistics (q (2) = 0.7613, r (2) = 0.927) has one hydrogen-bond acceptor, two hydrophobic features and two ring aromatic features. Furthermore, comparing those two models, the preferable AHHRR.1321 was employed as a novel searching tool for chemical databases to conduct virtual screening for new potential lead candidates. Consequently, refined Lipinski 'rule of five' and ADME properties were utilized as a filter to reduce less drug-like molecules. Among the hits, 10 non-steroidal compounds with good fitness score and physicochemical properties were identified.