%0 Journal Article
%T Combined 3D QSAR Based Virtual Screening and Molecular Docking Study of Some Selected PDK-1 Kinase Inhibitors
%A Shalini Singh
%A Pradeep Srivastava
%J Journal of Computational Medicine
%D 2014
%I Hindawi Publishing Corporation
%R 10.1155/2014/563080
%X Phosphoinositide-dependent kinase-1 (PDK-1) is an important therapeutic target for the treatment of cancer. In order to identify the important chemical features of PDK-1 inhibitors, a 3D QSAR pharmacophore model was developed based on 21 available PDK-1 inhibitors. The best pharmacophore model (Hypo1) exhibits all the important chemical features required for PDK-1 inhibitors. The correlation coefficient, root mean square deviation (RMSD), and cost difference were 0.96906, 1.0719, and 168.13, respectively, suggesting a good predictive ability of the model (Hypo1) among all the ten pharmacophore models that were analyzed. The best pharmacophore model (Hypo1) was further validated by Fisher¡¯s randomization method (95%), test set method , and the decoy set with the goodness of fit (0.73). Further, this validated pharmacophore model Hypo1 was used as a 3D query to screen the molecules from databases like NCI database and Maybridge. The resultant hit compounds were subsequently subjected to filtration by Lipinski¡¯s rule of five as well as the ADMET study. Docking study was done to refine the retrieved hits and as a result to reduce the rate of false positive. Best hits will further be subjected to in vitro study in future. 1. Introduction Protein kinases are critical components of cellular signal transduction cascades [1]. Over 500 protein kinases in the human genome have been reported till date and they are considered as the second largest group of drug targets [2, 3]. Phosphoinositide-dependent kinase-1 (PDK-1), a 63£¿kDa serine/threonine kinase, is a major player in the PI3-kinase signaling pathway that regulates gene expression, cell cycle, growth, and proliferation [4¨C11]. PDK-1 is also termed as the ¡®¡®master kinase¡¯¡¯ because it phosphorylates highly conserved serine or threonine residues in the T-loop (or activation loop) of numerous AGC kinases, including PKB/AKT, PKC, p70S6K, SGK, and PDK-1 itself [12]. Although precise regulatory mechanisms vary, in the case of PKB/AKT, activation by PDK-1 is critically dependent on prior PI3 kinase activation and the presence of phosphatidylinositol-(3,4,5)-triphosphate (PIP3). A significant proportion (40¨C50%) of all tumors involve mutations in PIP3-3-phosphatase (PTEN) [13¨C15], which result in elevated levels of PIP3 and enhanced activation of PKB/AKT, p70S6K, and SGK. The inhibitors of PDK-1 could potentially provide valuable therapeutic agents for the treatment of cancer. Recognition process between ligand and model is based on spatial distribution of certain structural features of active site being complimentary
%U http://www.hindawi.com/journals/jcm/2014/563080/