Combined 3D-QSAR modeling and molecular docking study on indolinone derivatives as inhibitors of 3-phosphoinositide-dependent protein kinase-1.
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.
AbdulHameed
Mohamed Diwan M
MD
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, Kentucky 40536, USA.
Hamza
Adel
A
Liu
Junjun
J
Zhan
Chang-Guo
CG
D064413:3-Phosphoinositide-Dependent Protein Kinases; D001665:Binding Sites / Q000187:drug effects; D003198:Computer Simulation; D021621:Imaging, Three-Dimensional; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D008956:Models, Chemical; D015394:Molecular Structure; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship
D007211:Indoles; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases