Studying the Binding Modes of Novel 2-Aminopyridine Derivatives as Effective and Selective c-Met Kinase Type 1 Inhibitors Using Molecular Modeling Approaches

The mesenchymal epithelial cell transforming factor c-Met, encoded by c-Met proto-oncogene and known as a high-affinity receptor for Hepatocyte Growth Factor (HGF), is one of the receptor tyrosine kinases (RTKs) members. The HGF/c-Met signaling pathway has close correlation with tumor growth, invasion and metastasis. Thus, c-Met kinase has emerged as a prominent therapeutic target for cancer drug discovery. Recently a series of novel 2-aminopyridine derivatives targeting c-Met kinase with high biological activity were reported. In this study, 3D quantitative structure-activity relationship (QSAR), molecular docking and molecular dynamics simulations (MD) were employed to research the binding modes of these inhibitors.The results show that both the atom-based and docking-based CoMFA (Q(2) = 0.596, R(2) = 0.950 in atom-based model and Q(2) = 0.563, R(2) = 0.985 in docking-based model) and CoMSIA (Q(2) = 0.646, R(2) = 0.931 in atom-based model and Q(2) = 0.568, R(2) = 0.983 in docking-based model) models own satisfactory performance with good reliabilities and powerful external predictabilities. Molecular docking study suggests that Tyr1230 and Arg1208 might be the key residues, and electrostatic and hydrogen bond interactions were shown to be vital to the activity, concordance with QSAR analysis. Then MD simulation was performed to further explore the binding mode of the most potent inhibitor. The obtained results provide important references for further rational design of c-Met Kinase type I inhibitors.