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Combined 3D-QSAR modeling and molecular docking study on indolinone derivatives as inhibitors of 3-phosphoinositide-dependent protein kinase-1.
J Chem Inf Model. 2008 Sep; 48(9):1760-72.JC

Abstract

3-Phosphoinositide-dependent protein kinase-1 (PDK1) is a promising target for developing novel anticancer drugs. In order to understand the structure-activity correlation of indolinone-based PDK1 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 3D-QSAR models, including the CoMFA model (r(2)=0.907; q(2)=0.737) and CoMSIA model (r(2)=0.991; q(2)=0.824), for predicting the biological activity of new compounds. The detailed microscopic structures of PDK1 binding with inhibitors have been studied by molecular docking. We have also developed docking-based 3D-QSAR models (CoMFA with q(2)=0.729; CoMSIA with q(2)=0.79). 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. This is the first report on 3D-QSAR modeling of PDK1 inhibitors. The satisfactory results strongly suggest that the developed 3D-QSAR models and the obtained PDK1-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

AbdulHameed MD
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, Kentucky 40536, USA.
Hamza A
No affiliation info available
Liu J
No affiliation info available
Zhan CG
No affiliation info available

MeSH

3-Phosphoinositide-Dependent Protein KinasesBinding SitesComputer SimulationImaging, Three-DimensionalIndolesModels, ChemicalMolecular StructureProtein-Serine-Threonine KinasesQuantitative Structure-Activity Relationship

Pub Type(s)

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

Language

eng

PubMed ID

18717540

Citation

AbdulHameed, Mohamed Diwan M., et al. "Combined 3D-QSAR Modeling and Molecular Docking Study On Indolinone Derivatives as Inhibitors of 3-phosphoinositide-dependent Protein Kinase-1." Journal of Chemical Information and Modeling, vol. 48, no. 9, 2008, pp. 1760-72.
AbdulHameed MD, Hamza A, Liu J, et al. Combined 3D-QSAR modeling and molecular docking study on indolinone derivatives as inhibitors of 3-phosphoinositide-dependent protein kinase-1. J Chem Inf Model. 2008;48(9):1760-72.
AbdulHameed, M. D., Hamza, A., Liu, J., & Zhan, C. G. (2008). Combined 3D-QSAR modeling and molecular docking study on indolinone derivatives as inhibitors of 3-phosphoinositide-dependent protein kinase-1. Journal of Chemical Information and Modeling, 48(9), 1760-72. https://doi.org/10.1021/ci800147v
AbdulHameed MD, et al. Combined 3D-QSAR Modeling and Molecular Docking Study On Indolinone Derivatives as Inhibitors of 3-phosphoinositide-dependent Protein Kinase-1. J Chem Inf Model. 2008;48(9):1760-72. PubMed PMID: 18717540.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Combined 3D-QSAR modeling and molecular docking study on indolinone derivatives as inhibitors of 3-phosphoinositide-dependent protein kinase-1. AU - AbdulHameed,Mohamed Diwan M, AU - Hamza,Adel, AU - Liu,Junjun, AU - Zhan,Chang-Guo, Y1 - 2008/08/22/ PY - 2008/8/23/pubmed PY - 2008/11/18/medline PY - 2008/8/23/entrez SP - 1760 EP - 72 JF - Journal of chemical information and modeling JO - J Chem Inf Model VL - 48 IS - 9 N2 - 3-Phosphoinositide-dependent protein kinase-1 (PDK1) is a promising target for developing novel anticancer drugs. In order to understand the structure-activity correlation of indolinone-based PDK1 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 3D-QSAR models, including the CoMFA model (r(2)=0.907; q(2)=0.737) and CoMSIA model (r(2)=0.991; q(2)=0.824), for predicting the biological activity of new compounds. The detailed microscopic structures of PDK1 binding with inhibitors have been studied by molecular docking. We have also developed docking-based 3D-QSAR models (CoMFA with q(2)=0.729; CoMSIA with q(2)=0.79). 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. This is the first report on 3D-QSAR modeling of PDK1 inhibitors. The satisfactory results strongly suggest that the developed 3D-QSAR models and the obtained PDK1-inhibitor binding structures are reasonable for the prediction of the activity of new inhibitors and in future drug design. SN - 1549-9596 UR - https://www.unboundmedicine.com/medline/citation/18717540/Combined_3D_QSAR_modeling_and_molecular_docking_study_on_indolinone_derivatives_as_inhibitors_of_3_phosphoinositide_dependent_protein_kinase_1_ L2 - https://doi.org/10.1021/ci800147v DB - PRIME DP - Unbound Medicine ER -