Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase with improved drug resistance properties. 1

Andrew L. Hopkins, Jingshan Ren, John Milton, Richard J. Hazen, Joseph H. Chan, David I. Stuart, David K. Stammers

    Research output: Contribution to journalArticle

    76 Citations (Scopus)

    Abstract

    We have used a structure-based approach to design a novel series of non-nucleoside inhibitors of HIV-1 RT (NNRTIs). Detailed analysis of a wide range of crystal structures of HIV-1 RT-NNRTI complexes together with data on drug resistance mutations has identified factors important for tight binding of inhibitors and resilience to mutations. Using this approach we have designed and synthesized a novel series of quinolone NNRTIs. Crystal structure analysis of four of these compounds in complexes with HIV-1 RT confirms the predicted binding modes. Members of this quinolone series retain high activity against the important resistance mutations in RT at Tyr181Cys and Leu100Ile.
    Original languageEnglish
    Pages (from-to)5912-5922
    Number of pages11
    JournalJournal of Medicinal Chemistry
    Volume47
    Issue number24
    DOIs
    Publication statusPublished - 2004

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