Structure-Aided Design
of Novel Inhibitors of HIV
Protease Based on a Benzodiazepine Scaffold
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Abstract
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[<i>b</i>,<i>e</i>][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[<i>b</i>,<i>e</i>][1,4]diazepinone analogues might represent
a potential new class of HIV PIs