Molecular modeling, docking and ADMET studies towards development of novel Disopyramide analogs for potential inhibition of human voltage gated sodium channel proteins



Khunza Meraj1, Manoj Kumar Mahto2, 6*, N Blessy Christina3, Nidhi Desai4, Sajad Shahbazi5 & Matcha Bhaskar6



1Department of Biotechnology, CMR College of Engineering & Technology, Hyderabad, AP, India; 2Department of Biotechnology, Acharya Nagarjuna University, Guntur, AP, India; 3Department of Human Genetics, Andhra University, Vishakhapatnam, AP, India; 4Department of Biotechnology, PESIT, Bangalore University, Bangalore, Karnataka, India; 5Department of Biotechnology, Kakatiya University, Warangal, AP, India; 6Division of Animal Biotechnology, Department of Zoology, Sri Venkateswara University, Tirupati, AP, India.


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Received September 23, 2012; Accepted September 27, 2012; Published November 23, 2012



The sodium “channelopathies” are the first among the ion channel diseases identified and have attracted widespread clinical and scientific interests. Human voltage gated sodium channels are sites of action of several antiarrhythmic drugs, local anesthetics and related antiepileptic drugs. The present study aims to optimize the activity of Disopyramide, by modification in its structures which may improve the drug action by reducing its side effects.Herein, we have selected Human voltage-gated sodium channel protein type 5 as a potent molecular target. Nearly eighty analogs of Disopyramide are designed and optimized. Thirty are selected for energy minimization using Discovery studio and the LigPrep 2.5. Prior to docking, the active sites of all the proteins are identified. The processing, optimization and minimization of all the proteins is done in Protein preparation wizard. The docking study is performed using the GLIDE. Finally top five ranked lead molecules with better dock scores are identified as having strong binding affinity to 2KAV protein than Disopyramide based on XP G scores. These five leads are further docked with other similar voltage gated sodium channel proteins (PDB IDs: 2KBI, 4DCK, 2L53 and 4DJC) and the best scoring analog with each protein is identified. Drug likeliness and comparative bioactivity analysis for all the analogs is done using QikProp 3.4. Results have shown that the top five lead molecules would have the potential to act as better drugs as compared to Disopyramide and would be of interest as promising starting point for designing compounds against various Sodium channelopathies.



Disopyramide, Human voltage-gated sodium channel proteins, Schrödinger 2011, QikProp 3.4, Docking, GLIDE, ADME, XP G Scores.



Meraj et al. Bioinformation 8(23): 1139-1146 (2012)

Edited by

P Kangueane






Biomedical Informatics



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