Structural Basis for the Improved Drug Resistance Profile of New Generation Benzophenone Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors

• Published in: Journal of medicinal chemistry Vol. 51; no. 16; pp. 5000 - 5008
• Main Authors: Ren, Jingshan, Chamberlain, Philip P, Stamp, Anna, Short, Steven A, Weaver, Kurt L, Romines, Karen R, Hazen, Richard, Freeman, Andrew, Ferris, Robert G, Andrews, C. Webster, Boone, Lawrence, Chan, Joseph H, Stammers, David K
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 28.08.2008
• Subjects: Amino Acid Substitution; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Benzophenones - chemistry; Benzophenones - pharmacology; Benzoxazines - chemistry; Biological and medical sciences; Crystallography, X-Ray; Drug Design; Drug Resistance, Viral - drug effects; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - chemistry; HIV Reverse Transcriptase - genetics; Medical sciences; Models, Molecular; Nevirapine - chemistry; Nitriles - pharmacology; Pharmacology. Drug treatments; Reverse Transcriptase Inhibitors - pharmacology; Structure-Activity Relationship; Sulfonamides - pharmacology; Benzophenone derivatives; Treatment resistance; RNA-directed DNA polymerase; HIV-1 virus; Enzyme; Transferases; Non nucleoside compound; Prediction; Retroviridae; Enzyme inhibitor; Inhibitor enzyme complex; Lentivirus; Modeling; Virus; Nucleotidyltransferases; Structure activity relation; Reverse transcriptase inhibitor; Molecular model; Antiviral; Human immunodeficiency virus
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm8004493

Owing to the emergence of resistant virus, next generation non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs) with improved drug resistance profiles have been developed to treat HIV infection. Crystal structures of HIV-1 RT complexed with benzophenones optimized for inhibition of HIV mutants that were resistant to the prototype benzophenone GF128590 indicate factors contributing to the resilience of later compounds in the series (GW4511, GW678248). Meta-substituents on the benzophenone A-ring had the designed effect of inducing better contacts with the conserved W229 while reducing aromatic stacking interactions with the highly mutable Y181 side chain, which unexpectedly adopted a “down” position. Up to four main-chain hydrogen bonds to the inhibitor also appear significant in contributing to resilience. Structures of mutant RTs (K103N, V106A/Y181C) with benzophenones showed only small rearrangements of the NNRTIs relative to wild-type. Hence, adaptation to a mutated NNRTI pocket by inhibitor rearrangement appears less significant for benzophenones than other next-generation NNRTIs.