Relationship of potency and resilience to drug resistant mutations for GW420867X revealed by crystal structures of inhibitor complexes for wild-type, Leu100Ile, Lys101Glu, and Tyr188Cys mutant HIV-1 reverse transcriptases

J Med Chem. 2007 May 17;50(10):2301-9. doi: 10.1021/jm061117m. Epub 2007 Apr 19.


The selection of drug resistant viruses is a major problem in efforts to combat HIV and AIDS, hence, new compounds are required. We report crystal structures of wild-type and mutant HIV-1 RT with bound non-nucleoside (NNRTI) GW420867X, aimed at investigating the basis for its high potency and improved drug resistance profile compared to the first-generation drug nevirapine. GW420867X occupies a smaller volume than many NNRTIs, yet accesses key regions of the binding pocket. GW420867X has few contacts with Tyr188, hence, explaining the small effect of mutating this residue on inhibitor-binding potency. In a mutated NNRTI pocket, GW420867X either remains in a similar position compared to wild-type (RT(Leu100Ile) and RT(Tyr188Cys)) or rearranges within the pocket (RT(Lys101Glu)). For RT(Leu100Ile), GW420867X does not shift position, in spite of forming different side-chain contacts. The small bulk of GW420867X allows adaptation to a mutated NNRTI binding site by repositioning or readjustment of side-chain contacts with only small reductions in binding affinity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemistry*
  • Binding Sites
  • Crystallography, X-Ray
  • Drug Resistance, Viral*
  • HIV Reverse Transcriptase / chemistry*
  • HIV Reverse Transcriptase / genetics*
  • HIV-1 / genetics*
  • Models, Molecular*
  • Molecular Structure
  • Mutation
  • Protein Binding
  • Quinoxalines / chemistry*
  • Reverse Transcriptase Inhibitors / chemistry*


  • Anti-HIV Agents
  • GW420867X
  • Quinoxalines
  • Reverse Transcriptase Inhibitors
  • HIV Reverse Transcriptase