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.
journal_name
J Chem Inf Modeljournal_title
Journal of chemical information and modelingauthors
AbdulHameed MD,Hamza A,Liu J,Zhan CGdoi
10.1021/ci800147vsubject
Has Abstractpub_date
2008-09-01 00:00:00pages
1760-72issue
9eissn
1549-9596issn
1549-960Xjournal_volume
48pub_type
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