3D-QSAR study of c-Src kinase inhibitors based on docking.

Cancer is a significant world health problem for which efficient therapies are in urgent demand. c-Src has emerged as an attractive target for drug discovery efforts toward antitumor therapies. Toward this target several series of c-Src inhibitors that showed activity in the assay have been reported. In this article, 3D-QSAR models have been built with 156 anilinoquinazoline and quinolinecarbonitrile derivative inhibitors by using CoMFA and CoMSIA methods. These studies indicated that the QSAR models were statistically significant with high predictabilities (CoMFA model, q(2) = 0.590, r(2) = 0.855; CoMSIA model, q(2) = 0.538, r(2) = 0.748). The details of c-Src kinase/inhibitor binding interactions in the crystal structure of complex provided new information for the design of new inhibitors. As a result, docking simulations were also conducted on the series of potent inhibitors. The flexible docking method, which was performed by the DOCK program, positioned all of the inhibitors into the active site to determine the probable binding conformation. The CoMFA and CoMSIA models based on the flexible docking conformations also yielded statistically significant and highly predictive QSAR models (CoMFA model, q(2) = 0.507, r(2) = 0.695; CoMSIA model, q(2) = 0.463, r(2) = 0.734). Our models would offer help to better comprehend the structure-activity relationships that exist for this class of compounds and also facilitate the design of novel inhibitors with good chemical diversity.