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. |