In silico approach for the identification of novel potent antidotes against botulinum neurotoxin serotypes A, B, E, and F.

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. The study was carried out with thirty-five designed ligands derived from the structure NSC1012 that consist of o-aminobenzoic acid, benzaldehyde and quinolone rings were docked against the catalytic domain of serotype BoNT/A; B; E and F, for the identification of the potent inhibitor. A computational approach used for virtual screening was performed by Molegro Virtual Docker (MVD) and AutoDock software. Analysis of molecular docking of the complex shows a high binding affinity for the target with Moldock score between -139.85 and -88.24 kcal mol-1and AutoDock score ranges between -11.65 to -5.30 kcal mol-1. These molecules could act as potential pan active inhibitors against botulinum neurotoxins. 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.