• Login
    View Item 
    •   Home
    • UMass Chan Faculty and Staff Research and Publications
    • UMass Chan Faculty and Researcher Publications
    • View Item
    •   Home
    • UMass Chan Faculty and Staff Research and Publications
    • UMass Chan Faculty and Researcher Publications
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of eScholarship@UMassChanCommunitiesPublication DateAuthorsUMass Chan AffiliationsTitlesDocument TypesKeywordsThis CollectionPublication DateAuthorsUMass Chan AffiliationsTitlesDocument TypesKeywords

    My Account

    LoginRegister

    Help

    AboutSubmission GuidelinesData Deposit PolicySearchingAccessibilityTerms of UseWebsite Migration FAQ

    Statistics

    Most Popular ItemsStatistics by CountryMost Popular Authors

    Evaluating the substrate-envelope hypothesis: structural analysis of novel HIV-1 protease inhibitors designed to be robust against drug resistance

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Authors
    Nalam, Madhavi N. L.
    Ali, Akbar
    Altman, Michael D.
    Reddy, G. S. Kiran Kumar
    Chellappan, Sripriya
    Kairys, Visvaldas
    Ozen, Aysegul
    Cao, Hong
    Gilson, Michael K.
    Tidor, Bruce
    Rana, Tariq M.
    Schiffer, Celia A.
    Show allShow less
    UMass Chan Affiliations
    Department of Biochemistry and Molecular Pharmacology
    Document Type
    Journal Article
    Publication Date
    2010-05-20
    Keywords
    Catalytic Domain
    Crystallography, X-Ray
    Drug Design
    *Drug Resistance, Viral
    HIV Protease
    HIV Protease Inhibitors
    HIV-1
    Humans
    Models, Molecular
    Protein Binding
    Protein Structure, Tertiary
    *Structure-Activity Relationship
    Molecular Biology
    Structural Biology
    Virology
    Show allShow less
    
    Metadata
    Show full item record
    Link to Full Text
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2863851
    Abstract
    Drug resistance mutations in HIV-1 protease selectively alter inhibitor binding without significantly affecting substrate recognition and cleavage. This alteration in molecular recognition led us to develop the substrate-envelope hypothesis which predicts that HIV-1 protease inhibitors that fit within the overlapping consensus volume of the substrates are less likely to be susceptible to drug-resistant mutations, as a mutation impacting such inhibitors would simultaneously impact the processing of substrates. To evaluate this hypothesis, over 130 HIV-1 protease inhibitors were designed and synthesized using three different approaches with and without substrate-envelope constraints. A subset of 16 representative inhibitors with binding affinities to wild-type protease ranging from 58 nM to 0.8 pM was chosen for crystallographic analysis. The inhibitor-protease complexes revealed that tightly binding inhibitors (at the picomolar level of affinity) appear to "lock" into the protease active site by forming hydrogen bonds to particular active-site residues. Both this hydrogen bonding pattern and subtle variations in protein-ligand van der Waals interactions distinguish nanomolar from picomolar inhibitors. In general, inhibitors that fit within the substrate envelope, regardless of whether they are picomolar or nanomolar, have flatter profiles with respect to drug-resistant protease variants than inhibitors that protrude beyond the substrate envelope; this provides a strong rationale for incorporating substrate-envelope constraints into structure-based design strategies to develop new HIV-1 protease inhibitors.
    Source

    J Virol. 2010 May;84(10):5368-78. Epub 2010 Mar 17. Link to article on publisher's site

    DOI
    10.1128/JVI.02531-09
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/26014
    PubMed ID
    20237088
    Notes

    Co-author Aysegul Ozen is a student in the Biochemistry & Molecular Pharmacology program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.

    Related Resources

    Link to Article in PubMed

    ae974a485f413a2113503eed53cd6c53
    10.1128/JVI.02531-09
    Scopus Count
    Collections
    UMass Chan Faculty and Researcher Publications
    Schiffer Lab Publications

    entitlement

    DSpace software (copyright © 2002 - 2023)  DuraSpace
    Lamar Soutter Library, UMass Chan Medical School | 55 Lake Avenue North | Worcester, MA 01655 USA
    Quick Guide | escholarship@umassmed.edu
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.