Design of putative c-Met inhibitors by sampling and clustering of its conformational space

Cancer is one of the leading reasons of morbidity and mortality worldwide. Among the well-known factors associated with tumor growth and metastases, the c-Met receptor is one of them [1]. Over expression of c-MET and its ligand (HGF) were appeared in several human cancers. Computational drug discovery demands to consider the conformational change of the both receptor and ligand [2]. Molecular dynamics (MD) simulation create trajectories of atomic positions as a function of time which is a representation of a given molecule’s accessible conformational ensemble. Also, the ligand inside the active site can effect on the protein conformation during the induced fit process. Therefore, we used 19 different complexes of c-Met in complex with potent inhibitors so that all of them showed U-shaped mode. MD simulations have been done for each of these complexes during 25 ns run time. The flexibility of c-Met was assessed by the analysis of the Cα root-mean-square fluctuation (RMSF). Some of residues with significant movements included: GLY1102 in 8 out of 19 codes and LYS1240, THR1241 in 5 codes. Also, the backbone Cα atoms of the residues TYR1230, ASP1222, PRO1158 and MET1160 which make the key hydrogen bond interactions with the ligand were quite fixed.

کلیدواژه ها:

QSAR ، c ، Met ، Cancer ، Molecular dynamics simulation.