Structure-based drug design of non-nucleoside inhibitors for wild-type and drug-resistant HIV reverse transcriptase.
The generation of anti-HIV agents using structure-based drug design methods has yielded a number of promising non-nucleoside inhibitors (NNIs) of HIV reverse transcriptase (RT). Recent successes in identifying potent NNIs are reviewed with an emphasis on the recent trend of utilizing a computer model of HIV RT to identify space in the NNI binding pocket that can be exploited by carefully chosen functional groups predicted to interact favorably with binding pocket residues. The NNI binding pocket model was used to design potent NNIs against both wild-type RT and drug-resistant RT mutants. Molecular modeling and score functions were used to analyze how drug-resistant mutations would change the RT binding pocket shape, volume, and chemical make-up, and how these changes could affect inhibitor binding. Modeling studies revealed that for an NNI of HIV RT to be active against RT mutants such as the especially problematic Y181C RT mutant, the following features are required: (a) the inhibitor should be highly potent against wild-type RT and therefore capable of tolerating a considerable activity loss against RT mutants (i.e. a picomolar-level inhibitor against wild-type RT may still be effective against RT mutants at nanomolar concentrations), (b) the inhibitor should maximize the occupancy in the Wing 2 region of the NNI binding site of RT, and (c) the inhibitor should contain functional groups that provide favorable chemical interactions with Wing 2 residues of wild-type as well as mutant RT. Our rationally designed NNI compounds HI-236, HI-240, HI-244, HI-253, HI-443, and HI-445 combine these three features and outperform other anti-HIV agents examined.
Mao
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Drug Discovery Program, Hughes Institute, St. Paul, MN 55113, USA.
Sudbeck
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Venkatachalam
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TK
Uckun
F M
FM
D019943:Amino Acid Substitution; D015195:Drug Design; D004352:Drug Resistance, Microbial; D006678:HIV / Q000187:drug effects / Q000201:enzymology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology
D018894:Reverse Transcriptase Inhibitors; D013844:Thiazoles; D014230:Triazoles; C062942:2-phenyl-6-(2'-(4'-(ethoxycarbonyl)thiazolyl))thiazolo(3,2-b)(1,2,4)triazole; D054303:HIV Reverse Transcriptase