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J Med Chem. 2004 Nov 18;47(24):5912-22.

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

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Division of Structural Biology, The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.


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.

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