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

J Med Chem. 2004 Nov 18;47(24):5912-22. doi: 10.1021/jm040071z.


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

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


  • Anti-HIV Agents
  • Quinolones
  • Reverse Transcriptase Inhibitors
  • HIV Reverse Transcriptase