Molecular modeling studies of vascular endothelial growth factor receptor tyrosine kinase inhibitors using QSAR and docking

The vascular endothelial growth factor (VEGF) and its receptor tyrosine kinases VEGFR-2 or kinase insert domain receptor (KDR) are attractive targets for the development of novel anticancer agents. In the present work, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of selective inhibitors of KDR. Docking studies were performed to explore the binding mode between all of the inhibitors and the KDR and produce the bioactive conformation of each compound in the whole dataset. Two conformer-based alignment strategies were employed to construct reliable 3D-QSAR models. The docked conformer-based alignment strategy gave the best 3D-QSAR models. The best CoMFA and CoMSIA models gave a cross-validated coefficient q(2) of 0.546 and 0.715, non-cross-validated r(2) values of 0.936 and 0.961, predicted r(2) values of 0.673 and 0.797, respectively. The information obtained from molecular modeling studies were very helpful to design some novel selective inhibitors of KDR with desired activity. (C) 2008 Elsevier Inc. All rights reserved.