Selection of herbal therapeutics against deltatoxin mediated Clostridial infections

Skariyachan, Sinosh; Mahajanakatti, Arpitha Badarinath; Sharma, Narasimha; Sevanan, Murugan

doi:10.6026/97320630006375

Cited by 3 publications

(4 citation statements)

References 19 publications

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“…The z-score can be used to filter less significant results or alternatively look for weak similarities. In spite of that, the relationship between backbone RMSD in Å and structure quality for X-ray structure ensemble for protein structure comparison showed that they were barely acceptable and have a very closely related to each other [ 19 , 36 ]. Therefore, the model predicted was acceptable.…”

Section: Discussionmentioning

confidence: 99%

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Homology modelling of CB1 receptor and selection of potential inhibitor against Obesity

Shrinivasan¹,

Skariyachan²,

Aparna³

et al. 2012

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Obesity and patient morbidity has become a health concern worldwide. Obesity is associated with over activity of the endocannabinoid system, which is involved in the regulation of appetite, lipogenesis and insulin resistance. Hypothalamic cannabinoid-1 receptor (CB1R) inverse agonists reduce body weight and improve cardiometabolic abnormalities in experimental and human obesity but displayed neuropsychiatric side effects. Hence, there is a need to develop therapeutics which employs blocking peripheral CB1 receptors and still achieve substantial weight loss. In view of the same, adipose tissue CB1 receptors are employed for this study since it is more specific in reducing visceral fat. Computer aided structure based virtual screening finds application to screen novel inhibitors and develop highly selective and potential drug. The rational drug design requires crystal structure for the CB1 receptor. However, the structure for the CB1 receptor is not available in its native form. Thus, we modelled the crystal structure using a lipid G-Protein coupled receptor (PDB: 3V2W, chain A) as template. Furthermore, we have screened a herbal ligand Quercetin [- 2- (3, 4-dihydroxyphenyl) - 3, 5, 7-trihydroxychromen-4-one] a flavonol present in Mimosa pudica based on its better pharmacokinetics and bioavailability profile. This ligand was selected as an ideal lead molecule. The docking of quercetin with CB1 receptor showed a binding energy of -6.56 Kcal/mol with 4 hydrogen bonds, in comparison to the known drug Rimonabant. This data finds application in proposing antagonism of CB1 receptor with Quercetin, for controlling obesity.

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Section: Discussionmentioning

confidence: 99%

“…The structure and chemical properties of the active site allow the recognition and binding of the ligand. The best conformations were screened in terms of lowest binding energy among several bioactive conformations generated by various iterations [ 36 ].…”

Section: Methodsmentioning

confidence: 99%

Homology modelling of CB1 receptor and selection of potential inhibitor against Obesity

Shrinivasan¹,

Skariyachan²,

Aparna³

et al. 2012

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“…Delta-toxin is one of the five haemolysins released by Clostridium perfringens which play a most important role in gas gangrene and gastroenteritis. The native structure of the delta-toxin is not yet reported in the structural databases (Skariyachan et al, 2011). C. perfringens has been shown to develop multiple drug resistance, indicating that the treatment for this bacterium is quite challenging.…”

Section: Natural Products As Potential Therapeutic Agents Against Clomentioning

confidence: 99%

Clostridium : Pathogenic Roles , Industrial Uses and Medicinal Prospects of Natural Products as Ameliorative Agents against Pathogenic Species

Num¹,

Useh²

2014

JJBS

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The genus Clostridium is made up of species that cause disease to both human beings and animals, with zoonotic species/strains playing critical roles in disease dynamics. Clostridial organisms posses pathogenic, therapeutic and industrial uses. Pathogenic clostridia cause lethal or life threatening infections that must be treated, while the industrial clostridia produce bio-fuels, to serve as alternative energy sources in the face of very high global prices of conventional fuels. Genetic engineering is currently developing novel strains by replacing or altering the gene configuration of pathogenic strains (gene knockout/down) to convert them to solvenogenic and non pathogenic strains for industrial uses. Therapeutic clostridia serve as vehicles for treatment of diseases, especially solid tumors. Because of the global problem of antibiotic resistance, which is a survival strategy by microbial pathogens, some of the well known chemotherapeutic protocols have failed and there is the need to evolve new treatment approaches, using novel agents that have superior mechanisms of action, compared to conventional antibiotics that are becoming inconsequential because of resistance. It is believed that natural products may be effective alternatives to resolving this puzzle, since they are cheaper, readily available and possibly effective against clostridial species. In this review article, the authors discussed some of the life threatening and solvenogenic clostridia and listed some natural products that may possibly be employed as drug targets for ameliorating the problem of resistance in the future, if their active principles are thoroughly researched. It is concluded that medical and veterinary research should be re-jigged to evolve active principles from natural products that are not so easily surmounted by the surge in drug resistant strains.

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“…Many herbal derived compounds have significant inhibitory and antimicrobial properties against a broad range of pathogenic microorganisms [ 8 ]. Our previous studies reported the applications of novel lead molecules against multidrug resistant Clostridium perfringens [ 9 ] and Staphylococcus aureus [ 10 ]. This study aims the selection of ligands from medicinal herbs and their utility as potential inhibitors against virulent toxins.…”

Section: Introductionmentioning

confidence: 99%

Structure based virtual screening of novel inhibitors against multidrug resistant superbugs

Skariyachan¹,

Mahajanakatti²,

Sharma³

et al. 2012

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Pathogenic microorganisms are persistently expressing resistance towards present generation antibiotics and are on the verge of joining the superbug family. Recent studies revealed that, notorious pathogens such as Salmonella typhi, Shigella dysenteriae and Vibrio cholerae have acquired multiple drug resistance and the treatment became a serious concern. This necessitates an alternative therapeutic solution. Present study investigates the utility of computer aided method to study the mechanism of receptor-ligand interactions and thereby inhibition of virulence factors (shiga toxin of Shigella dysenteriae, cholera toxin of Vibrio cholerae and hemolysin-E of Salmonella typhi) by novel phytoligands. The rational designs of improved therapeutics require the crystal structure for the drug targets. The structures of the virulent toxins were identified as probable drug targets. However, out of the three virulent factors, the structure for hemolysin-E is not yet available in its native form. Thus, we tried to model the structure by homology modeling using Modeller 9v9. After extensive literature survey, we selected 50 phytoligands based on their medicinal significance and drug likenesses. The receptor-ligands interactions between selected leads and toxins were studied by molecular docking using Auto Dock 4.0. We have identified two novel sesquiterpenes, Cadinane [(1S, 4S, 4aS, 6S, 8aS)- 4- Isopropyl- 1, 6- dimethyldecahydronaphthalene] and Cedrol [(8α)-Cedran-8-ol] against Shiga (binding energy -5.56 kcal/mol) and cholera toxins (binding energy -5.33 kcal/mol) respectively which have good inhibitory properties. Similarly, a natural Xanthophyll, Violaxanthin [3S, 3'S, 5R, 5'R, 6S, 6'S)-5, 5', 6, 6'-Tetrahydro-5, 6:5', 6'-diepoxy-β, β-carotene-3, 3'-diol] was identified as novel therapeutic lead for hemolysin-E (binding energy of –5.99 kcal/mol). This data provide an insight for populating the pool of novel inhibitors against various drug targets of superbugs when all current generation drugs seem to have failed.

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Selection of herbal therapeutics against deltatoxin mediated Clostridial infections

Cited by 3 publications

References 19 publications

Homology modelling of CB1 receptor and selection of potential inhibitor against Obesity

Homology modelling of CB1 receptor and selection of potential inhibitor against Obesity

Clostridium : Pathogenic Roles , Industrial Uses and Medicinal Prospects of Natural Products as Ameliorative Agents against Pathogenic Species

Structure based virtual screening of novel inhibitors against multidrug resistant superbugs

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