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 based on their binding
affinities and ADMET analysis. A computational approach for docking 35
designed ligands to the catalytic domain of serotype BoNT/A; B; E and F,
using Molegro Virtual Docker (MVD) and AutoDock suite was performed. The
screening of the best ‘hits’ among the docked complexes was done on the
basis of least docking score and common ligands, in both the programs.
Analysis of molecular docking of the complexes shows a high binding
affinity for the target with Moldock score between -139.85 and -88.24
kcal mol . Total five SMNPIs i.e., A9, A14, A15, A18
and A36 provided better binding affinities with the target protein
BoNT/A (-109.17, -107.95, -103.12, -108.29, and -112.38 kcal mol
), whereas for BoNT/B ligands A6, A10, and A31 has
showed score of -112.56, -123.93 and -115.13 kcal mol
. Ligands A6, A12, A18, and A24 exhibited the
docking score ranged from -117.20 to -132.19 kcal mol
for BoNT/E, and for BoNT/F, only two ligands
namely, A4 and A32 appeared to be potential inhibitors with the score of
(-115.41, and -117.99 kcal mol ). 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, in
this study we identified ‘hits’ that could be further progressed for
experimental studies leading to develop drug against botulism.