Discovery of novel inhibitors for c-Met by virtual screening and pharmacophore analysis

Abstract

The overexpression of human c-Met tyrosine kinase induces the tumor proliferation and migration. Commercial drug is still not available for inhibiting this target. The structure of human c-Met was simulated and validated by molecular modeling. Compounds from our laboratory database, including natural products and anticancer agents, were employed for the docking analysis. De Novo drug design was further performed for three compounds with highest DockScore value to discover the novel inhibitors. Through the adsorption, distribution, metabolism, excretion and toxicity (ADMET) descriptor, only compounds A 2, B 3, C 2 and C 5 were selected. Through the pharmacophore analysis, ARG1086, HIS1088, ARG1208, ASN1209, ALA1226, ARG1227, ASP1228, TYR1230, and GLU1233 were suggested as the key residues because of strong pharmacophore features. In addition, the pharmacophore features of candidates consisted with the active site properties. The added fragments produced the strong interaction with the surrounding residues and yielded hydrogen bonds (HBs). Thus, the interaction energy between the ligand and the receptor was enhanced. Besides, the values of several scoring functions (PLP1, PLP2, and DockScore) of candidates were comparatively higher than compounds A, B, C, and Kirin. According to the aforementioned analyses, compounds A, A 2, B, B 3, C, C 2 and C 5 were suggested as the potent c-Met inhibitors. Besides, the scaffolds of compounds A, B, and C provided the direction for further drug design.