Iman Mansi *, Mahmoud A. Al-Sha'er*, Nizar Mhaidat and Mutasem Taha Pages 476 - 485 ( 10 )
Background: Phosphoinositide-Dependent Kinase-1 (PDK1) is a serine/threonine kinase, which belongs to AGC kinase family required by cancer cells.
Methods: Pharmacophoric space of 86 PDK1 inhibitors using six diverse sets of inhibitors was explored to identify high-quality pharmacophores. The best combination of pharmacophoric models and physicochemical descriptors was selected by genetic algorithm-based QSAR analysis that can elucidate the variation of bioactivity within the training inhibitors. Two successful orthogonal pharmacophores emerged in the optimum QSAR equation (r2 69 = 0.90, r2 LOO= 0.86, F= 51.92, r2 PRESS against 17 test inhibitors = 0.79). Receiver Operating Characteristic (ROC) curve analyses were used to estimate the QSAR-selected pharmacophores.
Results: 5 out of 11 compounds tested had shown potential intracellular PDK1 inhibition with the highest inhibition percent for compounds 92 and 93 as follows; 90 and 92% PDK1 inhibition, respectively.
Conclusion: PDK1 inhibitors are potential anticancer agents that can be discovered by combination method of ligand based design with QSAR and ROC analysis.
PDK1, anticancer, 3D-QSAR, pharmacophores, ROC analysis, ligand based design.
Faculty of Pharmaceutical Sciences, The Hashemite University, P.O. Box 330127 Zarqa, 13133 , Faculty of Pharmacy, Zarqa University, Zarqa, 13132, Clinical Pharmacy Department, Faculty of Pharmacy, Jordan University of Science & Technology, Irbid, Drug Design Center, Faculty of Pharmacy, University of Jordan, Amman