Botulinum neurotoxins are the most poisonous substances reported and listed in category ‘A’ of biowarfare agent. These neurotoxins cause flaccid paralysis of muscles by inhibiting acetylcholine release at the neuromuscular junction, and leads to death. The light chain (catalytic domain) is responsible for cleavage of SNAREs and inhibition of its activity stops the progress of neuroparalysis. Serotype identification is a time-consuming process; hence development of inhibitor against human botulism causing serotypes will be advantageous. Computer assisted screening approaches have been proved a proficient in silico method in the drug discovery and development. In present study, ligand-based in silico method was applied to identify the “hits” against human intoxicating BoNTs. A computational approach using Molegro Virtual Docker (MVD) and AutoDock tool for docking catalytic domain of serotype BoNT/A; B; E and F with 34 designed ligands derived from NSC1012 was performed. Analysis of molecular docking of the complex shows a high binding affinity for the target (Moldock score between -139.85 and -88.24 kcal mol-1 ,whereas the AutoDock score ranges between -11.65 to -5.30 kcal mol-1).Three SMNPIs i.e., A11, A18, and A20 provided better binding affinities with the target proteins BoNT/A (-109.78, -108.29, and – 125.30 kcal mol-1), BoNT/B (-130.43, -131.93, and -120.39 kcal mol-1), BoNT/E (-138.02, -132.19, and -116.86kcal mol-1), and BoNT/F (-124.82, -139.85, and -120.69 kcal mol-1) and could be potential pan active inhibitors. The designed ligands were expected to be less toxic considering the Lipinski, Ghose, Veber and Egan rules with a bioavailability score of 0.56. Therefore, this study provides ‘hits’ that could be further progressed for experimental studies and lead to develop new antidotes for botulism.