Structure-aided design of novel inhibitors of HIV protease based on a benzodiazepine scaffold
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
23050738
DOI
10.1021/jm301249q
Knihovny.cz E-resources
- MeSH
- Benzodiazepines chemistry MeSH
- HIV Infections drug therapy enzymology virology MeSH
- HIV-1 drug effects MeSH
- HIV Protease chemistry metabolism MeSH
- HIV Protease Inhibitors chemical synthesis pharmacology MeSH
- Catalytic Domain MeSH
- Catalysis MeSH
- Protein Conformation MeSH
- Crystallography, X-Ray MeSH
- Humans MeSH
- Models, Molecular MeSH
- Molecular Structure MeSH
- Peptide Fragments pharmacology MeSH
- Drug Design * MeSH
- Hydrogen Bonding MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Benzodiazepines MeSH
- HIV Protease MeSH
- HIV Protease Inhibitors MeSH
- Peptide Fragments MeSH
HIV protease is a primary target for the design of virostatics. Screening of libraries of non-peptide low molecular weight compounds led to the identification of several new compounds that inhibit HIV PR in the low micromolar range. X-ray structure of the complex of one of them, a dibenzo[b,e][1,4]diazepinone derivative, showed that two molecules of the inhibitor bind to the PR active site. Covalent linkage of two molecules of such a compound by a two-carbon linker led to a decrease of the inhibition constant of the resulting compound by 3 orders of magnitude. Molecular modeling shows that these dimeric inhibitors form two crucial hydrogen bonds to the catalytic aspartates that are responsible for their improved activity compared to the monomeric parental building blocks. Dibenzo[b,e][1,4]diazepinone analogues might represent a potential new class of HIV PIs.
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