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Structure-aided design of novel inhibitors of HIV protease based on a benzodiazepine scaffold

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]d...

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Bibliographic Details
Main Authors: Schimer, Jiří (Author) , Oberwinkler, Heike (Author) , Kräusslich, Hans-Georg (Author)
Format: Article (Journal)
Language:English
Published: October 11, 2012
In: Journal of medicinal chemistry
Year: 2012, Volume: 55, Issue: 22, Pages: 10130-10135
ISSN:1520-4804
DOI:10.1021/jm301249q
Online Access:Verlag, Volltext: http://dx.doi.org/10.1021/jm301249q
Verlag, Volltext: https://doi.org/10.1021/jm301249q
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Author Notes:Jiří Schimer, Petr Cígler, Jan Veselý, Klára Grantz Šašková, Martin Lepšík, Jiří Brynda, Pavlína Řezáčová, Milan Kožíšek, Ivana Císařová, Heike Oberwinkler, Hans-Georg Kraeusslich, and Jan Konvalinka
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Summary: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.
Item Description:Gesehen am 07.05.2018
Physical Description:Online Resource
ISSN:1520-4804
DOI:10.1021/jm301249q

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