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The c-Met tyrosine kinase plays an important role in human cancers. Preclinical studies demonstrated that c-Met is over-expressed, mutated and amplified in a variety of human tumor types and design of more potent c-Met inhibitors is a priority. In this study, 14 molecular dynamics simulations of potent type II c-Met inhibitors were run to resolve the critical interactions responsible for high affinity of ligands towards c-Met considering the essential flexibility of protein-ligand interactions. Residues Phe1223 and Tyr1159, involved in pi-pi interactions were recognized as the most effective residues in the ligand binding in terms of binding free energies. Hydrogen bond interaction with Met1160 was also found necessary for effective type II ligand binding to c-Met.
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