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.
From: Division of Structural Biology, The Wellcome Trust Centre for Human Genetics, Henry Wellcome Building for Genomic Medicine, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, United Kingdom.
Journal of medicinal chemistry
- Publish Date: May 2007
- ISSN: 0022-2623
- Volume: 50
- Issue: 10
- Pages: 2301-9
- Medium: Print
- Language: English
- Citation (JAMA): Ren Jingshan, Nichols Charles E, Chamberlain Philip P, et al. 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. May 2007;50:2301-9
Abstract
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.
Mesh Headings (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
Check for Full Text / PubMed Unique Identifier (PMID): 17441703
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