Structural basis for the improved drug resistance profile of new generation benzophenone non-nucleoside HIV-1 reverse transcriptase inhibitors.

Abstract

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.

• Authors: Jingshan Ren, Philip P Chamberlain, Anna Stamp, Steven A Short, Kurt L Weaver, Karen R Romines, Richard Hazen, Andrew Freeman, Robert G Ferris, C Webster Andrews, Lawrence Boone, Joseph H Chan, David K Stammers
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 51 Issue 16 Pg. 5000-8 (Aug 28 2008) ISSN: 1520-4804 [Electronic] United States
• PMID: 18665583 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Alkynes
• Benzophenones
• Benzoxazines
• Cyclopropanes
• GW 678248
• Nitriles
• Reverse Transcriptase Inhibitors
• Sulfonamides
• Nevirapine
• reverse transcriptase, Human immunodeficiency virus 1
• HIV Reverse Transcriptase
• efavirenz

Topics

• Alkynes
• Amino Acid Substitution
• Benzophenones (chemistry, pharmacology)
• Benzoxazines (chemistry)
• Crystallography, X-Ray
• Cyclopropanes
• Drug Design
• Drug Resistance, Viral (drug effects)
• HIV Reverse Transcriptase (antagonists & inhibitors, chemistry, genetics)
• Models, Molecular
• Nevirapine (chemistry)
• Nitriles (pharmacology)
• Reverse Transcriptase Inhibitors (pharmacology)
• Structure-Activity Relationship
• Sulfonamides (pharmacology)