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Structure based virtual screening of novel inhibitors against multidrug resistant superbugs

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 dru...

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Autores principales: Skariyachan, Sinosh, Mahajanakatti, Arpitha Badarinath, Sharma, Narasimha, Karanth, Shraddha, Rao, Shruthi, Rajeswari, Narayanappa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Biomedical Informatics 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3374372/
https://www.ncbi.nlm.nih.gov/pubmed/22715312
http://dx.doi.org/10.6026/97320630008420
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author Skariyachan, Sinosh
Mahajanakatti, Arpitha Badarinath
Sharma, Narasimha
Karanth, Shraddha
Rao, Shruthi
Rajeswari, Narayanappa
author_facet Skariyachan, Sinosh
Mahajanakatti, Arpitha Badarinath
Sharma, Narasimha
Karanth, Shraddha
Rao, Shruthi
Rajeswari, Narayanappa
author_sort Skariyachan, Sinosh
collection PubMed
description 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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spelling pubmed-33743722012-06-19 Structure based virtual screening of novel inhibitors against multidrug resistant superbugs Skariyachan, Sinosh Mahajanakatti, Arpitha Badarinath Sharma, Narasimha Karanth, Shraddha Rao, Shruthi Rajeswari, Narayanappa Bioinformation Hypothesis 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. Biomedical Informatics 2012-05-15 /pmc/articles/PMC3374372/ /pubmed/22715312 http://dx.doi.org/10.6026/97320630008420 Text en © 2012 Biomedical Informatics This is an open-access article, which permits unrestricted use, distribution, and reproduction in any medium, for non-commercial purposes, provided the original author and source are credited.
spellingShingle Hypothesis
Skariyachan, Sinosh
Mahajanakatti, Arpitha Badarinath
Sharma, Narasimha
Karanth, Shraddha
Rao, Shruthi
Rajeswari, Narayanappa
Structure based virtual screening of novel inhibitors against multidrug resistant superbugs
title Structure based virtual screening of novel inhibitors against multidrug resistant superbugs
title_full Structure based virtual screening of novel inhibitors against multidrug resistant superbugs
title_fullStr Structure based virtual screening of novel inhibitors against multidrug resistant superbugs
title_full_unstemmed Structure based virtual screening of novel inhibitors against multidrug resistant superbugs
title_short Structure based virtual screening of novel inhibitors against multidrug resistant superbugs
title_sort structure based virtual screening of novel inhibitors against multidrug resistant superbugs
topic Hypothesis
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3374372/
https://www.ncbi.nlm.nih.gov/pubmed/22715312
http://dx.doi.org/10.6026/97320630008420
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