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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.

Original publication

DOI

10.1021/jm061117m

Type

Journal article

Journal

J Med Chem

Publication Date

17/05/2007

Volume

50

Pages

2301 - 2309

Keywords

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