3D-QSAR based pharmacophore modeling and virtual screening for identification of novel G protein-coupled receptor40 agonists

Pharmacophore models of G protein-coupled receptor40 (GPR40) agonists were developed using Discovery Studio V2.1. One hydrogen bond acceptor and three hydrophobic features, Hypo 1 which was the best hypothesis, had a correlation co-efficient of 0.971, cost difference of 73.041, and RMSD 0.680. This model was validated by test set, Fischer randomization test and decoy set. Subsequently, Hypo 1 was employed as a 3D query to identify potent molecules from chembridge database. 21 compounds were identified with estimated EC₅₀ less than 500 nM. Seven top-scored hit compounds were chosen for further evaluation in FLIPR assay and two compounds were discovered as potent GPR40 agonists.