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Meraj K, Mahto MK, Christina NB, et al. Molecular modeling, docking and ADMET studies towards development of novel Disopyramide analogs for potential inhibition of human voltage gated sodium channel proteins. Bioinformation. 2012;8(23):1139-46doi: 10.6026/97320630081139.
Meraj, K., Mahto, M. K., Christina, N. B., Desai, N., Shahbazi, S., & Bhaskar, M. (2012). Molecular modeling, docking and ADMET studies towards development of novel Disopyramide analogs for potential inhibition of human voltage gated sodium channel proteins. Bioinformation, 8(23), 1139-46. https://doi.org/10.6026/97320630081139
Meraj, Khunza, et al. "Molecular modeling, docking and ADMET studies towards development of novel Disopyramide analogs for potential inhibition of human voltage gated sodium channel proteins." Bioinformation vol. 8,23 (2012): 1139-46. doi: https://doi.org/10.6026/97320630081139
Meraj K, Mahto MK, Christina NB, Desai N, Shahbazi S, Bhaskar M. Molecular modeling, docking and ADMET studies towards development of novel Disopyramide analogs for potential inhibition of human voltage gated sodium channel proteins. Bioinformation. 2012;8(23):1139-46. doi: 10.6026/97320630081139. Epub 2012 Nov 23. PMID: 23275710; PMCID: PMC3530882.
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Bioinformation. 2012;8(23):1139-46. doi: 10.6026/97320630081139. Epub 2012 Nov 23.

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

Bioinformation

Khunza Meraj, Manoj Kumar Mahto, N Blessy Christina, Nidhi Desai, Sajad Shahbazi, Matcha Bhaskar

Affiliations

  1. Department of Biotechnology, CMR College of Engineering & Technology, Hyderabad, AP, India.

PMID: 23275710 PMCID: PMC3530882 DOI: 10.6026/97320630081139

Abstract

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.

Keywords: ADME; Disopyramide; Docking; GLIDE; Human voltage-gated sodium channel proteins; QikProp 3.4; Schrödinger 2011; XP G Scores

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