Repository logo
 
Publication

Molecular details of INH-C-10 binding to wt KatG and Its S315T mutant

2015-03Journal article Restricted access
Simple item page
dc.contributor.authorTeixeira, Vitor H.
dc.contributor.authorVentura, Cristina
dc.contributor.authorElvas Leitao, Ruben
dc.contributor.authorRàfols, Clara
dc.contributor.authorBosch, Elisabeth
dc.contributor.authorMartins, Filomena
dc.contributor.authorMachuqueiro, Miguel
dc.date.accessioned2016-04-28T10:31:18Z
dc.date.available2016-04-28T10:31:18Z
dc.date.issued2015-03
dc.description.abstractIsoniazid (INH) is still one of the two most effective antitubercular drugs and is included in all recommended multitherapeutic regimens. Because of the increasing resistance of Mycobacterium tuberculosis to INH, mainly associated with mutations in the katG gene, new INH-based compounds have been proposed to circumvent this problem. In this work, we present a detailed comparative study of the molecular determinants of the interactions between wt KatG or its S315T mutant form and either INH or INH-C10, a new acylated INH derivative. MD simulations were used to explore the conformational space of both proteins, and results indicate that the S315T mutation did not have a significant impact on the average size of the access tunnel in the vicinity of these residues. Our simulations also indicate that the steric hindrance role assigned to Asp137 is transient and that electrostatic changes can be important in understanding the enzyme activity data of mutations in KatG. Additionally, molecular docking studies were used to determine the preferred modes of binding of the two substrates. Upon mutation, the apparently less favored docking solution for reaction became the most abundant, suggesting that S315T mutation favors less optimal binding modes. Moreover, the aliphatic tail in INH-C10 seems to bring the hydrazine group closer to the heme, thus favoring the apparent most reactive binding mode, regardless of the enzyme form. The ITC data is in agreement with our interpretation of the C10 alkyl chain role and helped to rationalize the significantly lower experimental MIC value observed for INH-C10. This compound seems to be able to counterbalance most of the conformational restrictions introduced by the mutation, which are thought to be responsible for the decrease in INH activity in the mutated strain. Therefore, INH-C10 appears to be a very promising lead compound for drug development.pt_PT
dc.identifier.citationTEIXEIRA, Vitor H.; [et al] - Molecular details of INH-C-10 binding to wt KatG and Its S315T mutant. Molecular Pharmaceutics. ISSN 1543-8384. Vol. 12, N.º 3 (2015), pp. 898-909pt_PT
dc.identifier.doi10.1021/mp500736npt_PT
dc.identifier.issn1543-8384
dc.identifier.issn1543-8392
dc.identifier.urihttp://hdl.handle.net/10400.21/6111
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherAmer Chemical Socpt_PT
dc.subjectTuberculosispt_PT
dc.subjectITCpt_PT
dc.subjectResistancept_PT
dc.subjectMolecular dockingpt_PT
dc.subjectNew inhibitorpt_PT
dc.subjectMolecular dynamicspt_PT
dc.titleMolecular details of INH-C-10 binding to wt KatG and Its S315T mutantpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage909pt_PT
oaire.citation.issue3pt_PT
oaire.citation.startPage898pt_PT
oaire.citation.titleMolecular Pharmaceuticspt_PT
oaire.citation.volume12pt_PT
person.familyNameElvas Leitao
person.familyNameRàfols
person.familyNameBosch
person.familyNameMachuqueiro
person.givenNameRuben
person.givenNameClara
person.givenNameElisabeth
person.givenNameMiguel
person.identifier1433605
person.identifier.ciencia-idF41B-8A26-88D4
person.identifier.ciencia-idD416-CB5B-AC3D
person.identifier.orcid0000-0002-2196-412X
person.identifier.orcid0000-0001-7811-986X
person.identifier.orcid0000-0002-7123-8759
person.identifier.orcid0000-0001-6923-8744
person.identifier.ridD-2452-2009
person.identifier.ridG-5109-2019
person.identifier.ridL-6528-2014
person.identifier.ridC-8012-2011
person.identifier.scopus-author-id55667178200
person.identifier.scopus-author-id6701690949
person.identifier.scopus-author-id7103323396
person.identifier.scopus-author-id57221975472
rcaap.rightsclosedAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication440b7129-d4d9-4225-a936-ca694c0984b6
relation.isAuthorOfPublicationb054c52c-b564-4031-acfc-72e54c275151
relation.isAuthorOfPublicationc2802314-4923-4b60-a62e-babe57ac7903
relation.isAuthorOfPublication3466459e-d41d-436c-9b36-7e73e9d9cc9a
relation.isAuthorOfPublication.latestForDiscoveryb054c52c-b564-4031-acfc-72e54c275151

Files

Original bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
Molecular details of INH-C-10 binding to wt KatG and Its S315T mutant.pdf
Size:
5.14 MB
Format:
Adobe Portable Document Format
Download
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
1.71 KB
Format:
Item-specific license agreed upon to submission
Description:
Download

Collections

ISEL - Eng. Quim. Biol. - Artigos