Computer aided identification of sodium channel blockers in the clinical treatment of epilepsy using molecular docking tools

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Title	Computer aided identification of sodium channel blockers in the clinical treatment of epilepsy using molecular docking tools
Authors	Uzma Shaheen¹, Jyothy Akka¹, Jitendra Singh Hinore³, Amandeep Girdhar³, Srinivas Bandaru^{1, 2}, Tharaparambil Gangadharan Sumithnath⁴, Anuraj Nayarisseri³* & Anjana Munshi⁵
Affiliation	¹Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Hyderabad – 500 016, Telangana, India; ²National Institute of Pharmaceutical Education and Research, Hyderabad – 500 037, Telangana, India; ³In silico Research Laboratory, Eminent Biosciences, Indore – 452 010, Madhya Pradesh, India; ⁴St. Martin’s Engineering College, Jawaharlal Nehru Technological University, Hyderabad -500 014, Telangana, India; ⁵Centre for Human Genetics, Central University of Punjab, Bathinda- 151 001, Punjab, India
Email	anuraj@eminentbio.com; *Corresponding author
Article Type	Hypothesis
Date	Received February 22, 2015; Accepted March 14, 2015; Published March 31, 2015
Abstract	Phenytoin (PHT) and Carbamazepine (CBZ) are excellent sodium channel blockers administered in clinical treatment of epileptic seizures. However, the narrow therapeutic range and limited pharmacokinetics of these drugs have raised serious concerns in the proper management of epilepsy. To overcome this, the present study attempts to identify a candidate molecule with superior pharmacological profile than PHT and CBZ through In silico approaches. PHT and CBZ served as query small molecules for Tanimoto based similarity search with a threshold of 95% against PubChem database. Aided by MolDock algorithm, high affinity similar compound against each query was retrieved. PHT and CBZ and their respective similar were further tested for toxicity profiles, LC 50 values and biological activity. Compounds, NSC403438 and AGN-PC-0BPCBP respectively similar to PHT and CBZ demonstrated higher affinity to sodium channel protein than their respective leads. Of particular relevance, NSC403438 demonstrated highest binding affinity bestowed with least toxicity, better LC 50 values and optimal bioactivity. NSC403438 was further mapped for its structure based pharmacophoric features. In the study, we report NSC403438 as potential sodium channel blocker as a better candidate than PHT and CBZ which can be put forth for pharmacodynamic and pharmacokinetic studies.
Keywords	Sodium channel blockers, Virtual Screening, Phenytoin, Carbamazepine, NSC403438 and AGN-PC-0BPCBP
Abbreviations	AEDs: Antiepileptic drugs, BLAST: Basic Local Alignment Search Tool, CBZ: Carbamazepine, GEFS+: Generalized Epilepsy with Febrile Seizures Plus, GPCR: G Protein Coupled Receptor, Nav: Sodium channel with specific voltage conduction, PDB: Protein Data Bank, PHT: Phenytoin, PIR: Protein Information resources, SAVES: Structural Analysis and Verification Server, VGSC: Voltage-gated Sodium channels
Citation	Shaheen et al. Bioinformation 11(3): 131-137 (2015)
Edited by	P Kangueane
ISSN	0973-2063
Publisher	Biomedical Informatics
License	This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.