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

• Published in: Journal of medicinal chemistry Vol. 50; no. 10; pp. 2301 - 2309
• Main Authors: Ren, Jingshan, Nichols, Charles E, Chamberlain, Philip P, Weaver, Kurt L, Short, Steven A, Chan, Joseph H, Kleim, Jörg-Peter, Stammers, David K
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 17.05.2007
• Subjects: Anti-HIV Agents - chemistry; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Binding Sites; Biological and medical sciences; Crystallography, X-Ray; Drug Resistance, Viral; HIV Reverse Transcriptase - chemistry; HIV Reverse Transcriptase - genetics; HIV-1 - genetics; Human immunodeficiency virus 1; Medical sciences; Models, Molecular; Molecular Structure; Mutation; Pharmacology. Drug treatments; Protein Binding; Quinoxalines - chemistry; Reverse Transcriptase Inhibitors - chemistry; Drug; RNA-directed DNA polymerase; HIV-1 virus; Enzyme; Transferases; Non nucleoside compound; Retroviridae; Enzyme inhibitor; Inhibitor enzyme complex; Binding site; Lentivirus; Biological activity; Virus; Resistance; Nucleotidyltransferases; Reverse transcriptase inhibitor; Antiviral; Inhibitor; Human immunodeficiency virus; Mutation; Crystalline structure
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm061117m

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.