Design of potent c-Met inhibitors by molecular fingerprints: a computational insight

Cancer is the most common deadly disease and a major public health problem worldwide. c-Met receptor is among the well-known factors associated with tumor growth and metastasis [1]. Aberrant activation of c-Met, frequently related to c-Met gene amplification, c-Met overexpression or mutations, has been reported in most solid tumors. Therefore, c-Met kinase has been chosen as a promising therapeutic target for various cancers. Herein, a QSAR study based on molecular fingerprints has been carried out for a set of 37 1H-pyrrolo [2,3-b] pyridine c-Met inhibitors [2]. The model was significant with R2=0.83 and R2pred=0.8. Based on obtained coefficients of fingerprints, several compounds have been designed and we predicted their activities by the QSAR model. One of them showed pIC50 more than 8.00. Therefore, we ran a 35 ns molecular dynamics (MD) simulation for this compound and the RMSF of the backbone Cα atoms for each protein residue was obtained during the equilibrium time range. No RMSF value greater than 2 nm for residues inside the active site was observed which shows that protein and ligand just moved slightly. Analysis of MD trajectory showed that two key hydrogen bond interactions including Lys1110 and Met1160 were stable during the equilibrium time range.

کلیدواژه ها:

QSAR ، c ، Met ، Cancer ، Molecular dynamics simulation