The first pharmacophore model for potent G protein-coupled receptor 119 agonist

G protein-coupled receptor 119 (GPR119) has emerged as arguably one of the most exciting targets for the treatment of type 2 diabetes mellitus in the new millennium. Pharmacophore models were developed by using Discovery Studio V2.1 with a training set of 24 GPR119 agonists. The best hypothesis consisting of five features, namely, two hydrogen bond acceptors and three hydrophobic features, has a correlation coefficient of 0.969, cost difference of 62.68, RMS of 0.653, and configuration cost of 15.24, suggesting that a highly predictive pharmacophore model was successfully obtained. The application of the model shows great success in predicting the activities of the 25 known GPR119 agonists in our test set with a correlation coefficient of 0.933.

Graphical abstractPharmacophore model was generated using HypoGen algorithm in DS v2.1. The well validated Hypo1 perfectly fits GPR119 agonist in trials.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► The first pharmacophore model for potent G protein-coupled receptor 119 agonist. ► A highly predictive pharmacophore model was successfully obtained. ► Hypo1 perfectly fits GSK-1292263 as a GPR119 agonist in trials. ► 20 compounds were selected as GPR119 agonists in virtual screening.