Article ID Journal Published Year Pages File Type
444504 Journal of Molecular Graphics and Modelling 2010 18 Pages PDF
Abstract

The vascular endothelial growth factor (VEGF) and its receptor tyrosine kinases VEGFR-2 are attractive targets for the development of novel anticancer agents. To understand the structure–activity correlation of 1,4-dihydroindeno[1,2-c]pyrazole-based VEGFR-2 inhibitors, we have carried out a combined molecular docking and three-dimensional quantitative structure–activity relationship (3D-QSAR) modeling study. The study has resulted in two types of satisfactory substructure-based 3D-QSAR models, including the CoMFA model (r2, 0.931; q2, 0.600) and CoMSIA model (r2, 0.928; q2, 0.569), for predicting the biological activity of new compounds. The detailed microscopic structures of VEGFR-2 binding with inhibitors have been studied by molecular docking. We have also developed docking based 3D-QSAR models (CoMFA with r2, 0.958; q2, 0.563; CoMSIA with r2, 0.965; q2, 0.567). The contour maps obtained from the 3D-QSAR models in combination with the docked binding structures help to better interpret the structure–activity relationship. All of the structural insights obtained from both the 3D-QSAR contour maps and molecular docking are consistent with the available experimental activity data. The satisfactory results strongly suggest that the developed 3D-QSAR models and the obtained VEGFR-2 inhibitor binding structures are reasonable for the prediction of the activity of new inhibitors and in future drug design.

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Physical Sciences and Engineering Chemistry Physical and Theoretical Chemistry
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