Please use this identifier to cite or link to this item: https://dspace.iiti.ac.in/handle/123456789/4012
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dc.contributor.authorSonavane, Avinashen_US
dc.date.accessioned2022-03-17T01:00:00Z-
dc.date.accessioned2022-03-17T15:31:20Z-
dc.date.available2022-03-17T01:00:00Z-
dc.date.available2022-03-17T15:31:20Z-
dc.date.issued2018-
dc.identifier.citationJagadeb, M., Rath, S. N., & Sonawane, A. (2018). Computational discovery of potent drugs to improve the treatment of pyrazinamide resistant mycobacterium tuberculosis mutants. Journal of Cellular Biochemistry, 119(9), 7328-7338. doi:10.1002/jcb.27033en_US
dc.identifier.issn0730-2312-
dc.identifier.otherEID(2-s2.0-85053494992)-
dc.identifier.urihttps://doi.org/10.1002/jcb.27033-
dc.identifier.urihttps://dspace.iiti.ac.in/handle/123456789/4012-
dc.description.abstractEmergence of multi-drug resistance tuberculosis has become a serious health problem globally. Accumulation of mutations in the drug target led to the development of multi-drug resistant mycobacterial strains that have made most of the conventional drugs ineffective. Hence, there is desperate need for the development of new therapeutic strategies. Here, we focused on the analysis of mutations in Mycobacterium tuberculosis (Mtb) PncA (pyrazinamidase) that is responsible for resistance against first-line anti-tuberculosis pyrazinamide (PZA) drug. First, PZA and its two isoforms were analyzed for their binding affinity toward ligand binding cavity of Mtb wild-type and mutant PncA proteins. The observations suggested that some drug resistant mutations cause strong binding of PncA with the active form of PZA and impair its release, which is required to inhibit the growth of Mtb. To improve the treatment of PZA resistant Mtb, high throughput virtual drug screening was performed to identify potent drug molecules from a library of compounds derived from ChEMBL database. From this library, we predicted a lead molecule (terta-butyl(2S,4S)-4-amino-2-cyclopropyl-6-(trifluoromethyl)-3,4-dihydro-2H-quinoline-1-carboxylate) to be more effective against PZA resistant Mtb strains in comparison to PZA. The lead molecule showed better drug-like properties such as high affinity and atomic interactions with wild-type and drug-resistant mutations in Mtb PncA proteins. Further, molecular dynamic simulation studies showed that this lead molecule has better conformational stability and compatibility with drug-resistant PncA proteins in comparison to PZA drug. We hypothesized that the predicted lead compound could be more effective, and thus may improve the treatment of PZA resistant tuberculosis. © 2018 Wiley Periodicals, Inc.en_US
dc.language.isoenen_US
dc.publisherWiley-Liss Inc.en_US
dc.sourceJournal of Cellular Biochemistryen_US
dc.subjectamidaseen_US
dc.subjectcytoplasm proteinen_US
dc.subjectnicotinamidaseen_US
dc.subjectpyrazinamidaseen_US
dc.subjectpyrazinamideen_US
dc.subjectquinoline derivativeen_US
dc.subjectterta butyl 4 amino 2 cyclopropyl 6 (trifluoromethyl) 3,4 dihydro 2h quinoline 1 carboxylateen_US
dc.subjecttuberculostatic agenten_US
dc.subjectunclassified drugen_US
dc.subjectamidaseen_US
dc.subjectliganden_US
dc.subjectPncA protein, Mycobacterium tuberculosisen_US
dc.subjectprotein bindingen_US
dc.subjectpyrazinamideen_US
dc.subjecttuberculostatic agenten_US
dc.subjectArticleen_US
dc.subjectbacterial growthen_US
dc.subjectbinding affinityen_US
dc.subjectbiocompatibilityen_US
dc.subjectchemical analysisen_US
dc.subjectclinical effectivenessen_US
dc.subjectcomparative studyen_US
dc.subjectcomputer modelen_US
dc.subjectconformational transitionen_US
dc.subjectdata baseen_US
dc.subjectdrug efficacyen_US
dc.subjectdrug identificationen_US
dc.subjectdrug potencyen_US
dc.subjectdrug resistant tuberculosisen_US
dc.subjectdrug screeningen_US
dc.subjectdrug stabilityen_US
dc.subjectgene mutationen_US
dc.subjecthigh throughput screeningen_US
dc.subjectligand bindingen_US
dc.subjectmolecular dockingen_US
dc.subjectmolecular dynamicsen_US
dc.subjectmultidrug resistanceen_US
dc.subjectMycobacterium tuberculosisen_US
dc.subjectnonhumanen_US
dc.subjectpoint mutationen_US
dc.subjectpriority journalen_US
dc.subjectprotein bindingen_US
dc.subjecttreatment indicationen_US
dc.subjectbinding siteen_US
dc.subjectchemistryen_US
dc.subjectdrug developmenten_US
dc.subjectdrug effecten_US
dc.subjectgeneticsen_US
dc.subjecthumanen_US
dc.subjectmolecular dynamicsen_US
dc.subjectmutationen_US
dc.subjectMycobacterium tuberculosisen_US
dc.subjectproceduresen_US
dc.subjectprotein foldingen_US
dc.subjectprotein secondary structureen_US
dc.subjectstructural homologyen_US
dc.subjecttuberculosisen_US
dc.subjectAmidohydrolasesen_US
dc.subjectAntitubercular Agentsen_US
dc.subjectBinding Sitesen_US
dc.subjectDrug Discoveryen_US
dc.subjectDrug Resistance, Multiple, Bacterialen_US
dc.subjectHumansen_US
dc.subjectLigandsen_US
dc.subjectMolecular Docking Simulationen_US
dc.subjectMolecular Dynamics Simulationen_US
dc.subjectMutationen_US
dc.subjectMycobacterium tuberculosisen_US
dc.subjectProtein Bindingen_US
dc.subjectProtein Foldingen_US
dc.subjectProtein Structure, Secondaryen_US
dc.subjectPyrazinamideen_US
dc.subjectStructural Homology, Proteinen_US
dc.subjectTuberculosisen_US
dc.titleComputational discovery of potent drugs to improve the treatment of pyrazinamide resistant Mycobacterium tuberculosis mutantsen_US
dc.typeJournal Articleen_US
Appears in Collections:Department of Biosciences and Biomedical Engineering

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