Takeda G-protein-coupled receptor 5 (TGR5) is emerging as an important and promising target for the development of anti-diabetic drugs. To understand the structural characteristics of TGR5 agonists, the common feature pharmacophore models were generated and molecular docking was performed. The ligand-based virtual screening combined with pharmacophore mapping and molecular docking was performed to identify novel nonsteroidal TGR5 agonists. Finally, 20 compounds were screened for in vitro TGR5 agonistic activity assay, and results showed most compounds exhibiting TGR5 agonistic activity at 40 μM. Among these compounds, V12 and V14 displayed obvious TGR5 agonist activity, with the EC50 values of 19.5 μM and 7.7 μM, respectively. Compounds V12 and V14 could be considered potential TGR5 agonist candidates and also may be used as initial hits for developing novel TGR5 agonists.
