Virtual screening based on pharmacophore model followed by docking simulation studies in search of potential inhibitors for p38 map kinase

Abstract

P38 mitogen-activated protein (MAP) kinase inhibitors are closely involved in the production of inflammatory cytokines. These compounds are considered promising therapeutic agents for chronic inflammatory disorders. In this study, a ligand-based pharmacophore model of p38 map kinase inhibitors was developed. The best five features pharmacophore model includes two hydrogen bond acceptors, two hydrophobic and an aromatic hydrophobic features, which has the highest correlation coefficient (0.822), cost difference (134.158), low root mean square (RMS) of error (1.315). As well as the developed model shows a high goodness of fit and enrichment factor. The pharmacophore hypothesis has been validated by using a series of similar structures with varying affinities for the p38 map kinase. It also has been employed as a search query in different database searching with the ultimate goal of finding novel compounds which have the possibility to be modified into novel lead molecules. As a result, some hit compounds were introduced as final candidates by employing virtual screening and molecular docking procedure simultaneously. The results from pharmacophore modeling and molecular docking are complementary to each other and could serve as a useful approach for the discovery of potent small molecules as p38 map kinase inhibitors.