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Ligand Based Pharmacophore Modeling Followed by Biological Screening Lead to Discovery of Novel PDK1 Inhibitors as Anticancer Agents

[ Vol. 20 , Issue. 4 ]


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

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