Combined 3D-QSAR modeling and molecular docking study on 1,4-dihydroindeno[1,2-c]pyrazoles as VEGFR-2 kinase inhibitors

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 (r(2), 0.931; q(2), 0.600) and CoMSIA model (r(2), 0.928; q(2), 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 r(2), 0.958; q(2), 0.563; CoMSIA with r(2), 0.965; q(2), 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. (C) 2010 Elsevier Inc. All rights reserved.