Though
tetanus is an old disease with well known medicines, its complications are still a serious issue worldwide.
Tetanus is mainly due to a powerful
neurotoxin,
tetanolysin-O, produced by a Gram positive anaerobic bacterium, Clostridium tetani. The toxin has a
thiol-activated
cytolysin which causes lysis of human platelets, lysosomes and a variety of subcellular membranes. The existing
therapy seems to have challenged as available
vaccines are not so effective and the bacteria developed resistance to many drugs. Computer aided approach is a novel platform to screen
drug targets and design potential inhibitors. The three dimensional structure of the toxin is essential for structure based
drug design. But the structure of
tetanolysin-O is not available in its native form. Moreover, the interaction and pharmacological activities of current drugs against
tetanolysin-O is not clear. Hence, there is need for three dimensional model of the toxin. The model was generated by homology modeling using crystal structure of
perfringolysin-O, chain-A (PDB ID: 1PFO) as the template. The modeled structure has 22.7% α helices, 27.51% β sheets and 41.75% random coils. A
thiol-activated
cytolysin was predicted in the region of 105 to 1579, which acts as a functional domain of the toxin. The hypothetical model showed the backbone root mean square deviation (RMSD) value of 0.6 Å and the model was validated by ProCheck. The Ramachandran plot of the model accounts for 92.3% residues in the most allowed region. The model was further refined by various tools and deposited to
Protein Model Database (PMDB ID: PM0077550). The model was used as the
drug target and the interaction of various lead molecules with
protein was studied by molecular docking. We have selected phytoligands based on literatures and pharmacophoric studies. The efficiency of herbal compounds and chemical leads was compared. Our study concluded that herbal derivatives such as
berberine (7, 8, 13, 13a-tetradehydro-9,10-dimethoxy-2,3 [methylenebis(oxy)] berbinium),
curcumin ((1E,6E)-1,7-bis (4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione),
coumarin (2H-chromen-2-one),
catechol (Benzene-1,2-diol) and diosphenol (2-hydroxy-3-methyl-6-propan-2-ylcyclohex-2-en-1-one) are the best inhibitors compared to known chemicals. Hence, these leads can be used as potential inhibitors against
tetanolysin.