In silico exploration of novel phytoligands against probable drug target of Clostridium tetani

Abstract

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.

Exploring insights for virulent gene inhibition of multidrug resistantSalmonella typhi,Vibrio cholerae, andStaphylococcus areusby potential phytoligands viain silicoscreening

“…V. cholerae also showed drug resistance to Trimethoprim. S. aureus showed multidrug resistance to present generation drugs such as Methicillin and Vancomycin (Skariyachan et al, 2012). Our previous results clearly indicate that these bacteria became resistant to conventionally used drugs and emerged as superbugs (multidrug-resistant organisms).…”

“…Hence, in the present study, we have focused to inhibit the virulent functions of the drug-resistant genes by novel phytoligands. Our previous studies proved the utility of computer-aided virtual screening toward many multidrug-resistant pathogens (Skariyachan et al, 2012). Several herbal substances are known to have vital inhibitory properties against various drug targets of many gastrointestinal pathogens (Eumkeb & Chukrathok 2013;Eumkeb, Siriwong, & Thumanu, 2012;Rúa et al, 2012;Schrader, 2010).…”

“…S. aureus showed resistance to conventionally used drugs such as Vancomycin, Methicillin, Oxacillin, Tetracycline, etc. Similarly, Salmonella sps showed resistance to Trimethoprim, Kanamycin, Cefoperazone, Cefotaxime, Cefixime, Moxifloxacin, Piperacillin/Tazobactam, Cotrimoxazole, Levofloxacin, Trimethoprim, and Ceftazidime (Skariyachan et al, 2012). These pathogens are responsible for adverse health implications in humans and animals.…”

Toxin-associated infectious diseases: tetanus, botulism and diphtheria

“…A transsynaptic transport of the intact toxin may lead to its dissemination into the CNS, but the toxin cannot pass the blood--brain barrier [13]. The role of tetanolysin is not fully known, but it may lead to cell lysis, thereby promoting local tissue damage and bacterial growth [14].…”

Challenges, Applications, and Recent Advances of Protein-Ligand Docking in Structure-Based Drug Design

“…The methodology behind building homology models is outside the scope of this review, but here we remark on the popularity of the approach in practice. It is notable that a number of recent successful virtual screening projects used homology models of the protein receptor, and for some the best template for homology modeling was fairly divergent from the target structure, in terms of percent sequence identity [126,127,128,129,130,131,132].…”