Design of Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase with Improved Drug Resistance Properties. 1

• Published in: Journal of medicinal chemistry Vol. 47; no. 24; pp. 5912 - 5922
• Main Authors: Hopkins, Andrew L, Ren, Jingshan, Milton, John, Hazen, Richard J, Chan, Joseph H, Stuart, David I, Stammers, David K
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 18.11.2004; Amer Chemical Soc
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Cell Line; Chemistry, Medicinal; Crystallography, X-Ray; Drug Design; Drug Resistance, Viral; HIV Reverse Transcriptase - chemistry; HIV Reverse Transcriptase - genetics; HIV Reverse Transcriptase - metabolism; HIV-1 - drug effects; HIV-1 - enzymology; Human immunodeficiency virus 1; Humans; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Molecular Structure; Mutation; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Quinolones - chemical synthesis; Quinolones - chemistry; Quinolones - pharmacology; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; Science & Technology; Structure-Activity Relationship; ANGSTROM RESOLUTION; SELECTIVE PRESSURE; GRIP REGION; BHAP U-90152; DNA-SYNTHESIS; HUMAN-IMMUNODEFICIENCY-VIRUS; RT INHIBITORS; TYPE-1; MUTATIONAL ANALYSIS; TEMPLATE-PRIMER UTILIZATION; RNA-directed DNA polymerase; HIV-1 virus; Nitrogen heterocycle; Non nucleoside compound; Lactam; Binding site; Modeling; Structure activity relation; Chlorine Organic compounds; Reverse transcriptase inhibitor; Molecular model; Bicyclic compound; Binding mode; Antiviral; Aromatic compound; Chemical synthesis; Quinolone derivatives; Treatment resistance; Ether; Enzyme; Transferases; Retroviridae; Enzyme inhibitor; Inhibitor enzyme complex; Lentivirus; X ray diffraction; In vitro; Virus; Nucleotidyltransferases; Human immunodeficiency virus; Mutation; Crystalline structure
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm040071z

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.