Structure–activity relationship and in silico development of c‐Met kinase inhibitors

Abstract

AbstractOverexpression and concomitant drug resistance of c‐Met kinase are strongly associated with poor prognosis in gastric carcinoma. This needs the further development of existing lead compounds against c‐Met. Herein, we conducted molecular modeling studies of 4‐phenoxypyridine derivatives as c‐Met kinase inhibitors using docking, molecular dynamics (MD), and binding energy estimation to examine receptor–ligand interaction, complex stability, and binding affinity. We developed statistically significant three‐dimensional structure–activity relationship models (3D‐QSAR) to correlate the physicochemical characteristics of the inhibitors with their biological activities. The field effects of the chemical descriptors were determined as contour polyhedrons and emphasized as SAR. Thirty new compounds were designed according to the SAR scheme, and their activities were predicted using the 3D‐QSAR model. The designed compounds with higher predicted pIC50 values than the most active compounds in the dataset were subjected to absolute binding free‐energy evaluation by free energy perturbation (FEP) method.