Title:Ligand Based Pharmacophore Modeling Followed by Biological Screening Lead to Discovery of Novel PDK1 Inhibitors as Anticancer Agents
Volume: 20
Issue: 4
Author(s): Iman Mansi *, Mahmoud A. Al-Sha'er*, Nizar Mhaidat and Mutasem Taha
Affiliation:
- Faculty of Pharmaceutical Sciences, The Hashemite University, P.O. Box 330127 Zarqa, 13133,Jordan
- Faculty of Pharmacy, Zarqa University, Zarqa, 13132,Jordan
Keywords:
PDK1, anticancer, 3D-QSAR, pharmacophores, ROC analysis, ligand based design.
Abstract:
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.