A Quest for New Antimalarial Agents with Improved Specificity Guided by Molecular Docking, 3D QSAR and Molecular Dynamics Simulation Studies

Janaiah Chevula, Saikrishna Balabadra, Sree Kanth Sivan and Vijjulatha Manga*

Molecular Modeling and Medicinal Chemistry Group, Department of Chemistry, University College of Science, Osmania University, Hyderabad-500 007, India

*Corresponding author: Fax: +91 40 27090020; Tel: +91 40 27682337; E-mail: vijjulathamanga@gmail.com


Chloroquine (CQ)-resistance strain of Plasmodium falciparum is posting as an alarming hitch in curing malarial disease. Efforts are on to overcome this drug resistance and to produce potential inhibitors. In this context, three-dimensional quantitative structure-activity relationship (3D-QSAR) and docking studies were extended out for recently reported 4-aminoquinoline rhodanine, 4-aminoquinoline tetrazoles, 4-anilinoquinoline triazines, 9-anilinoacridine triazines. The model generated showed good correlation coefficients r2 (0.961 and 0.965) and test set prediction coefficients r2 (0.600 and 0.620); all reinforce showed the good predictive competence of the QSAR model derived. Based on outcome of results we designed new inhibitors. These newly designed molecules were docked into active site of protein. The docking results revealed that these molecules not only interact specifically with Glu 122 in the NADH binding pocket as that of best active compound but also showed additional interactions with Leu 115. Further, molecular dynamics simulations were also carried which reinforced the docking results and showed that the newly designed molecules formed more stable complexes when compared to existing ligands. Furthermore these molecules retained interactions with active site amino acid residue Glu 122 for more percentage of simulation time which is crucial for enhancing inhibitory activity. Therefore it can be concluded that these newly designed molecules can further be modified so as to generate more potent anti malarial lead structures in near future.


4-Aminoquinoline hybrids, pf3D7 Strain, Molecular docking, 3D-QSAR, Molecular dynamics simulation.

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