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