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Combined 3D-QSAR modeling and molecular docking study on 1,4-dihydroindeno[1,2-c]pyrazoles as VEGFR-2 kinase inhibitors.
J Mol Graph Model. 2010 Aug 24; 29(1):54-71.JM

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 (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.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Zeng H
Key Laboratory of radiopharmaceuticals of Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, China.
Zhang H
No affiliation info available

MeSH

Binding SitesCrystallography, X-RayInhibitory Concentration 50Models, MolecularProtein ConformationProtein Kinase InhibitorsPyrazolesQuantitative Structure-Activity RelationshipStatic ElectricityVascular Endothelial Growth Factor Receptor-2

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20471293

Citation

Zeng, Huahui, and Huabei Zhang. "Combined 3D-QSAR Modeling and Molecular Docking Study On 1,4-dihydroindeno[1,2-c]pyrazoles as VEGFR-2 Kinase Inhibitors." Journal of Molecular Graphics & Modelling, vol. 29, no. 1, 2010, pp. 54-71.
Zeng H, Zhang H. Combined 3D-QSAR modeling and molecular docking study on 1,4-dihydroindeno[1,2-c]pyrazoles as VEGFR-2 kinase inhibitors. J Mol Graph Model. 2010;29(1):54-71.
Zeng, H., & Zhang, H. (2010). Combined 3D-QSAR modeling and molecular docking study on 1,4-dihydroindeno[1,2-c]pyrazoles as VEGFR-2 kinase inhibitors. Journal of Molecular Graphics & Modelling, 29(1), 54-71. https://doi.org/10.1016/j.jmgm.2010.04.004
Zeng H, Zhang H. Combined 3D-QSAR Modeling and Molecular Docking Study On 1,4-dihydroindeno[1,2-c]pyrazoles as VEGFR-2 Kinase Inhibitors. J Mol Graph Model. 2010 Aug 24;29(1):54-71. PubMed PMID: 20471293.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Combined 3D-QSAR modeling and molecular docking study on 1,4-dihydroindeno[1,2-c]pyrazoles as VEGFR-2 kinase inhibitors. AU - Zeng,Huahui, AU - Zhang,Huabei, Y1 - 2010/04/24/ PY - 2009/10/20/received PY - 2010/03/05/revised PY - 2010/04/18/accepted PY - 2010/5/18/entrez PY - 2010/5/18/pubmed PY - 2010/12/28/medline SP - 54 EP - 71 JF - Journal of molecular graphics & modelling JO - J Mol Graph Model VL - 29 IS - 1 N2 - 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. SN - 1873-4243 UR - https://www.unboundmedicine.com/medline/citation/20471293/Combined_3D_QSAR_modeling_and_molecular_docking_study_on_14_dihydroindeno[12_c]pyrazoles_as_VEGFR_2_kinase_inhibitors_ DB - PRIME DP - Unbound Medicine ER -