title: Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase with improved drug resistance properties. 1.
abstract: 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.
authors.affiliation: Division of Structural Biology, The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Hopkins
authors.forename: Jingshan
authors.initials: J
authors.lastname: Ren
authors.forename: John
authors.initials: J
authors.lastname: Milton
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Hazen
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Chan
authors.forename: David I
authors.initials: DI
authors.lastname: Stuart
authors.forename: David K
authors.initials: DK
authors.lastname: Stammers
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D015363:Quinolones; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase