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

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

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.

Highlights

In silico approaches include homology modeling, Docking, quantitative structure activity relationships, virtual ligand screening, similarity and pharmacophore searching, data mining, and data analysis tools are becoming increasingly important in new drug design and have been frequently used in the discovery and optimization of novel molecules with enhanced affinity and specificity for the selected therapeutic targets [1,2,3,4]
Five lead molecules with CH2NH2, OCH2CH3, OSO2, CH2CH2CH3, and OSO2CH3 substitutionswere showing higher XP G Scores of -3.6, -3.2, -2.87, -2.76 & -2.74 respectively than Disopyramide (G Score = -2.63) as a result of docking of 30 analogs and Disopyramide with 2KAV protein. These five leads along with Disopyramide when further docked with 2KBI, 4DCK, 2L53 & 4DJC have shown better dock scores compared to Disopyramide
A thorough study was carried out over thirty computationally designed Disopyramide analogs using various software programs with the goal of identifying potential lead molecules that bind to the human voltage-gated sodium channel protein(VGSC) type 5 relying on computational docking and pharmacological properties prediction with Grid – based Ligand Docking with Energetics (GLIDE) of Schrodinger 2011 and QikProp 3.4 respectively

Summary

Introduction

In silico approaches include homology modeling, Docking, quantitative structure activity relationships, virtual ligand screening, similarity and pharmacophore searching, data mining, and data analysis tools are becoming increasingly important in new drug design and have been frequently used in the discovery and optimization of novel molecules with enhanced affinity and specificity for the selected therapeutic targets [1,2,3,4]. Further computational prediction of pharmacokinetic parameters like Absorption, Distribution, Metabolism and Excretion (ADME) & toxicity studies have become increasingly important in drug selection and promotion process and are promising tools for early screening of potential drug candidates [6]. Main side effects are Ventricular tachycardia, ventricular fibrillation, QT interval prolongation, myocardial depression, hypotension, AV block; anti-muscarinic effects including dry mouth, blurred vision, urinary retention, gastrointestinal irritation. Main drug interactions comprise increased risk of ventricular arrhythmias with amiodarone, antiarrhythmics, torsadogenic agents, diuretics (due to hypokalemia) increased plasma concentration with macrolides decreased plasma concentration with rifampicin; increased myocardial depression with anti-arrhythmics and beta-blockers

Methods

Results

Conclusion