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dc.contributor.authorChellappan, Sripriya
dc.contributor.authorKairys, Visvaldas
dc.contributor.authorFernandes, Miguel X.
dc.contributor.authorSchiffer, Celia A.
dc.contributor.authorGilson, Michael K.
dc.date2022-08-11T08:08:01.000
dc.date.accessioned2022-08-23T15:39:18Z
dc.date.available2022-08-23T15:39:18Z
dc.date.issued2007-05-03
dc.date.submitted2010-02-05
dc.identifier.citationProteins. 2007 Aug 1;68(2):561-7. <a href="http://dx.doi.org/10.1002/prot.21431">Link to article on publisher's site</a>
dc.identifier.issn1097-0134 (Electronic)
dc.identifier.doi10.1002/prot.21431
dc.identifier.pmid17474129
dc.identifier.urihttp://hdl.handle.net/20.500.14038/26135
dc.description.abstractCrystallographic data show that various substrates of HIV protease occupy a remarkably uniform region within the binding site; this region has been termed the substrate envelope. It has been suggested that an inhibitor that fits within the substrate envelope should tend to evade viral resistance because a protease mutation that reduces the affinity of the inhibitor will also tend to reduce the affinity of substrate, and will hence decrease the activity of the enzyme. Accordingly, inhibitors that fit the substrate envelope better should be less susceptible to clinically observed resistant mutations, since these must also allow substrates to bind. The present study describes a quantitative measure of the volume of a bound inhibitor falling outside the substrate envelope, and observes that this quantity correlates with the inhibitor's losses in affinity to clinically relevant mutants. This measure may thus be useful as a penalty function in the design of robust HIV protease inhibitors.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=17474129&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1002/prot.21431
dc.subjectBinding Sites
dc.subjectCrystallography, X-Ray
dc.subjectHIV Protease
dc.subjectHIV Protease Inhibitors
dc.subjectHIV-1
dc.subjectKinetics
dc.subjectModels, Molecular
dc.subjectMolecular Conformation
dc.subjectMutation
dc.subjectRecombinant Proteins
dc.subjectSubstrate Specificity
dc.subjectBiochemistry, Biophysics, and Structural Biology
dc.subjectPharmacology, Toxicology and Environmental Health
dc.titleEvaluation of the substrate envelope hypothesis for inhibitors of HIV-1 protease
dc.typeJournal Article
dc.source.journaltitleProteins
dc.source.volume68
dc.source.issue2
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/bmp_pp/73
dc.identifier.contextkey1134046
html.description.abstract<p>Crystallographic data show that various substrates of HIV protease occupy a remarkably uniform region within the binding site; this region has been termed the substrate envelope. It has been suggested that an inhibitor that fits within the substrate envelope should tend to evade viral resistance because a protease mutation that reduces the affinity of the inhibitor will also tend to reduce the affinity of substrate, and will hence decrease the activity of the enzyme. Accordingly, inhibitors that fit the substrate envelope better should be less susceptible to clinically observed resistant mutations, since these must also allow substrates to bind. The present study describes a quantitative measure of the volume of a bound inhibitor falling outside the substrate envelope, and observes that this quantity correlates with the inhibitor's losses in affinity to clinically relevant mutants. This measure may thus be useful as a penalty function in the design of robust HIV protease inhibitors.</p>
dc.identifier.submissionpathbmp_pp/73
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.source.pages561-7


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