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KMID : 0043320150380081434
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Archives of Pharmacal Research
2015 Volume.38 No. 8 p.1434 ~ p.1442
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3D-QSAR study of tetrahydro-3H-imidazo[4,5-c]pyridine derivatives as VEGFR-2 kinase inhibitors using various charge schemes
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Balupuri Anand
Balasubramanian Pavithra K.
Cho Seung-Joo
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Abstract
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Vascular endothelial growth factor-2 receptor (VEGFR-2) kinase is a promising target for the development of novel anticancer drugs. Three-dimensional quantitative structure?activity relationship (3D-QSAR) study was performed on a series of tetrahydro-3H-imidazo[4,5-c]pyridine derivatives to understand the structural basis for VEGFR-2 inhibitory activity. Several 3D-QSAR models were developed using various partial atomic charge schemes. Comparative molecular field analysis (CoMFA) and Comparative molecular similarity indices analysis (CoMSIA) methods were employed to derive these models. The CoMFA models performed better than the CoMSIA models. The reliable CoMFA model was obtained with the Gasteiger?Marsili charge scheme. The model produced statistically significant results with a cross-validated correlation coefficient (q2) of 0.635 and a coefficient of determination (r2) of 0.930. The model showed reasonable predictive power with predictive correlation coefficient ( r2predrpred2 ) of 0.582. Robustness of the model was further checked by leave-five-out cross-validation, bootstrapping and progressive scrambling analysis. The model was found to be statistically robust and expected to assist in the design of novel compounds with enhanced VEGFR-2 inhibitory activity.
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KEYWORD
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3D-QSAR, VEGFR-2 kinase inhibitors, Partial charges, CoMFA, CoMSIA
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