3D-QSAR studies on c-Src kinase inhibitors and docking analyses of a potent dual kinase inhibitor of c-Src and c-Abl kinases Original Research Article

Three-dimensional quantitative structure–activity relationship (3D-QSAR) analyses were carried out on quinazoline, quinoline, and cyanoquinoline derivatives inhibiting c-Src kinase. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) 3D-QSAR models were developed. The conventional r2 values for CoMFA and CoMSIA are 0.93 and 0.89, respectively. In addition, a homology model of c-Src kinase with the activation loop resembling the active conformation was constructed using the crystal structure of the kinase domain of Lck. The ATP binding pocket of the active form of c-Src is similar to that of the c-Abl kinase in which the activation loop resembles that of an active form. One of the potent c-Src and c-Abl dual kinase inhibitors (77 or SKI-606) was docked inside the active sites of both c-Src and c-Abl. The orientation and hydrogen bonding interactions of 77 are similar in both kinases. The results of 3D-QSAR analyses and structure based studies will be useful for the design of novel c-Src and c-Abl dual kinase inhibitors.