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

摘要

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 (Hypol),consisting of five features,namely,two hydrogen bond acceptors and three hydrophobic features,has a high correlation coefficient of 0.969,a cost difference of 62.68,a low 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 GPRll9 agonists in our test set with a correlation coefficient of 0.933 and a cross validation of 95％ confidence level.The results demonstrate that the hypothesis derived in this study can be considered as a useful and reliable tool in identifying structurally diverse compounds with desired biological activity.