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dc.contributor.authorAltman, Michael D.
dc.contributor.authorAli, Akbar
dc.contributor.authorReddy, G. S. Kiran Kumar
dc.contributor.authorNalam, Madhavi N. L.
dc.contributor.authorAnjum, Saima G.
dc.contributor.authorCao, Hong
dc.contributor.authorChellappan, Sripriya
dc.contributor.authorKairys, Visvaldas
dc.contributor.authorFernandes, Miguel X.
dc.contributor.authorGilson, Michael K.
dc.contributor.authorSchiffer, Celia A.
dc.contributor.authorRana, Tariq M.
dc.contributor.authorTidor, Bruce
dc.date2022-08-11T08:08:01.000
dc.date.accessioned2022-08-23T15:39:17Z
dc.date.available2022-08-23T15:39:17Z
dc.date.issued2008-04-17
dc.date.submitted2010-02-05
dc.identifier.citationJ Am Chem Soc. 2008 May 14;130(19):6099-113. Epub 2008 Apr 16. <a href="http://dx.doi.org/10.1021/ja076558p">Link to article on publisher's site</a>
dc.identifier.issn1520-5126 (Electronic)
dc.identifier.doi10.1021/ja076558p
dc.identifier.pmid18412349
dc.identifier.urihttp://hdl.handle.net/20.500.14038/26130
dc.description.abstractThe acquisition of drug-resistant mutations by infectious pathogens remains a pressing health concern, and the development of strategies to combat this threat is a priority. Here we have applied a general strategy, inverse design using the substrate envelope, to develop inhibitors of HIV-1 protease. Structure-based computation was used to design inhibitors predicted to stay within a consensus substrate volume in the binding site. Two rounds of design, synthesis, experimental testing, and structural analysis were carried out, resulting in a total of 51 compounds. Improvements in design methodology led to a roughly 1000-fold affinity enhancement to a wild-type protease for the best binders, from a Ki of 30-50 nM in round one to below 100 pM in round two. Crystal structures of a subset of complexes revealed a binding mode similar to each design that respected the substrate envelope in nearly all cases. All four best binders from round one exhibited broad specificity against a clinically relevant panel of drug-resistant HIV-1 protease variants, losing no more than 6-13-fold affinity relative to wild type. Testing a subset of second-round compounds against the panel of resistant variants revealed three classes of inhibitors: robust binders (maximum affinity loss of 14-16-fold), moderate binders (35-80-fold), and susceptible binders (greater than 100-fold). Although for especially high-affinity inhibitors additional factors may also be important, overall, these results suggest that designing inhibitors using the substrate envelope may be a useful strategy in the development of therapeutics with low susceptibility to resistance.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=18412349&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1021/ja076558p
dc.subjectAlgorithms
dc.subjectCarbamates
dc.subjectCrystallography, X-Ray
dc.subjectDrug Design
dc.subjectDrug Resistance, Viral
dc.subjectHIV Protease
dc.subjectHIV Protease Inhibitors
dc.subjectHIV-1
dc.subjectKinetics
dc.subjectModels, Molecular
dc.subjectStructure-Activity Relationship
dc.subjectSulfonamides
dc.subjectBiochemistry, Biophysics, and Structural Biology
dc.subjectPharmacology, Toxicology and Environmental Health
dc.titleHIV-1 protease inhibitors from inverse design in the substrate envelope exhibit subnanomolar binding to drug-resistant variants
dc.typeJournal Article
dc.source.journaltitleJournal of the American Chemical Society
dc.source.volume130
dc.source.issue19
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/bmp_pp/69
dc.identifier.contextkey1134042
html.description.abstract<p>The acquisition of drug-resistant mutations by infectious pathogens remains a pressing health concern, and the development of strategies to combat this threat is a priority. Here we have applied a general strategy, inverse design using the substrate envelope, to develop inhibitors of HIV-1 protease. Structure-based computation was used to design inhibitors predicted to stay within a consensus substrate volume in the binding site. Two rounds of design, synthesis, experimental testing, and structural analysis were carried out, resulting in a total of 51 compounds. Improvements in design methodology led to a roughly 1000-fold affinity enhancement to a wild-type protease for the best binders, from a Ki of 30-50 nM in round one to below 100 pM in round two. Crystal structures of a subset of complexes revealed a binding mode similar to each design that respected the substrate envelope in nearly all cases. All four best binders from round one exhibited broad specificity against a clinically relevant panel of drug-resistant HIV-1 protease variants, losing no more than 6-13-fold affinity relative to wild type. Testing a subset of second-round compounds against the panel of resistant variants revealed three classes of inhibitors: robust binders (maximum affinity loss of 14-16-fold), moderate binders (35-80-fold), and susceptible binders (greater than 100-fold). Although for especially high-affinity inhibitors additional factors may also be important, overall, these results suggest that designing inhibitors using the substrate envelope may be a useful strategy in the development of therapeutics with low susceptibility to resistance.</p>
dc.identifier.submissionpathbmp_pp/69
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.source.pages6099-113


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