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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 publication

DOI

10.1021/jm040071z

Type

Journal article

Journal

J Med Chem

Publication Date

18/11/2004

Volume

47

Pages

5912 - 5922

Keywords

Anti-HIV Agents, Cell Line, Crystallography, X-Ray, Drug Design, Drug Resistance, Viral, HIV Reverse Transcriptase, HIV-1, Humans, Models, Molecular, Molecular Structure, Mutation, Quinolones, Reverse Transcriptase Inhibitors, Structure-Activity Relationship