Structural basis for the improved drug resistance profile of new generation benzophenone non-nucleoside HIV-1 reverse transcriptase inhibitors.
作者： Jingshan Ren , Philip P. Chamberlain , Anna Stamp , Steven A. Short , Kurt L. Weaver
DOI: 10.1021/JM8004493
关键词:
摘要: Owing to the emergence of resistant virus, next generation non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs) with improved drug resistance profiles have been developed treat infection. Crystal structures HIV-1 RT complexed benzophenones optimized for inhibition mutants that were prototype benzophenone GF128590 indicate factors contributing resilience later compounds in series (GW4511, GW678248). Meta-substituents on A-ring had designed effect inducing better contacts conserved W229 while reducing aromatic stacking interactions highly mutable Y181 side chain, which unexpectedly adopted a "down" position. Up four main-chain hydrogen bonds inhibitor also appear significant resilience. Structures mutant RTs (K103N, V106A/Y181C) showed only small rearrangements NNRTIs relative wild-type. Hence, adaptation mutated NNRTI pocket by rearrangement appears less than other next-generation NNRTIs.
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