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.
MeSH terms
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Anti-HIV Agents / chemical synthesis*
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Anti-HIV Agents / chemistry
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Anti-HIV Agents / pharmacology
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Cell Line
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Crystallography, X-Ray
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Drug Design
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Drug Resistance, Viral*
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HIV Reverse Transcriptase / chemistry*
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HIV Reverse Transcriptase / genetics
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HIV Reverse Transcriptase / metabolism
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HIV-1 / drug effects
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HIV-1 / enzymology
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Humans
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Models, Molecular
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Molecular Structure
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Mutation
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Quinolones / chemical synthesis*
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Quinolones / chemistry
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Quinolones / pharmacology
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Reverse Transcriptase Inhibitors / chemical synthesis*
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Reverse Transcriptase Inhibitors / chemistry
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Reverse Transcriptase Inhibitors / pharmacology
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Structure-Activity Relationship
Substances
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Anti-HIV Agents
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Quinolones
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Reverse Transcriptase Inhibitors
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HIV Reverse Transcriptase