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Toward the design of mutationā€resistant enzyme inhibitors: further evaluation of the substrate envelope hypothesis

2009Journal article Open access
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dc.contributor.authorKairys, Visvaldas
dc.contributor.authorGilson, Michael K.
dc.contributor.authorLather, Viney
dc.contributor.authorSchiffer, Celia A.
dc.contributor.authorFernandes, Miguel X.
dc.date.accessioned2023-02-07T12:28:54Z
dc.date.available2023-02-07T12:28:54Z
dc.date.issued2009
dc.description.abstractPrevious studies have shown the usefulness of the substrate envelope concept in the analysis and prediction of drug resistance profiles for human immunodeficiency virus protease mutants. This study tests its applicability to several other thera peutic targets: Abl kinase, chitinase, thymidylate synthase, dihydrofolate reductase, and neuramini dase. For the targets where many (ā€”6) mutation data are available to compute the average mutation sen sitivity of inhibitors, the total volume of an inhibitor molecule that projects outside the substrate enve lope Vout, is found to correlate with average muta tion sensitivity. Analysis of a locally computed volume suggests that the same correlation would hold for the other targets, if more extensive muta tion data sets were available. It is concluded that the substrate envelope concept offers a promising and easily implemented computational tool for the design of drugs that will tend to resist muta tions. Software implementing these calculations is provided with the ā€™Supporting Informationā€™.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationKairys, V., Gilson, M. K., Lather, V., Schiffer, C. A., & Fernandes, M. X. (2009). Toward the design of mutationā€resistant enzyme inhibitors: further evaluation of the substrate envelope hypothesis. Chemical biology & drug design, 74(3), 234-245.pt_PT
dc.identifier.doi10.1111/j.1747-0285.2009.00851.xpt_PT
dc.identifier.urihttp://hdl.handle.net/10400.13/5009
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherWileypt_PT
dc.relationCOMPUTATIONAL MODELING OF PHOSPHODIESTERASE 3 INHIBITORS
dc.relationDESIGN AND DEVELOPMENT OF PPARDELTA SELECTIVE LIGANDS USING STRUCTURE BASED AND LIGAND BASED COMPUTATIONAL APPROACHES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.subjectMutation resistancept_PT
dc.subjectSubstrate envelopept_PT
dc.subject.pt_PT
dc.subjectFaculdade de CiĆŖncias Exatas e da Engenhariapt_PT
dc.titleToward the design of mutationā€resistant enzyme inhibitors: further evaluation of the substrate envelope hypothesispt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleCOMPUTATIONAL MODELING OF PHOSPHODIESTERASE 3 INHIBITORS
oaire.awardTitleDESIGN AND DEVELOPMENT OF PPARDELTA SELECTIVE LIGANDS USING STRUCTURE BASED AND LIGAND BASED COMPUTATIONAL APPROACHES
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/PIDDAC/SFRH%2FBPD%2F41787%2F2007/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/PIDDAC/SFRH%2FBPD%2F30954%2F2006/PT
oaire.citation.endPage245pt_PT
oaire.citation.issue3pt_PT
oaire.citation.startPage234pt_PT
oaire.citation.titleChemical Biology & Drug Designpt_PT
oaire.citation.volume74pt_PT
oaire.fundingStreamPIDDAC
oaire.fundingStreamPIDDAC
person.familyNameKairys
person.familyNameFernandes
person.givenNameVisvaldas
person.givenNameMiguel Xavier
person.identifierK-9893-2013
person.identifier.ciencia-idA716-F916-AFB2
person.identifier.ciencia-idED1D-3C7A-467C
person.identifier.orcid0000-0002-5427-0175
person.identifier.orcid0000-0002-1840-616X
person.identifier.ridA-4373-2013
person.identifier.scopus-author-id6602925161
person.identifier.scopus-author-id35466972500
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundaĆ§Ć£o para a CiĆŖncia e a Tecnologia
project.funder.nameFundaĆ§Ć£o para a CiĆŖncia e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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relation.isAuthorOfPublication8dab9a0d-f44a-4d2d-b9b1-7b3145162ca3
relation.isAuthorOfPublication.latestForDiscovery43821a45-10cf-4dbd-bc5a-fa88d146fc36
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