期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 13, 期 15, 页码 4704-4712出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2005.04.065
关键词
3D-QSAR; homology modeling; docking; c-Src kinase inhibitors; Src-Abl dual kinase inhibitors
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 r(2) 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-AbI 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-AbI dual kinase inhibitors. (c) 2005 Elsevier Ltd. All rights reserved.
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