Structure-Aided Design of Novel Inhibitors of HIV Protease Based on a Benzodiazepine Scaffold

Schimer, Jiří; Cígler, Petr; Veselý, J.; Grantz Šašková, Klára; Lepšík, Martin; Brynda, Jiří; Řezáčová, Pavlína; Kožíšek, Milan; Císařová, I.; Oberwinkler, H.; Kraeusslich, H. G.; Konvalinka, Jan

doi:https://dx.doi.org/10.1021/jm301249q

Number of the records: 1

Structure-Aided Design of Novel Inhibitors of HIV Protease Based on a Benzodiazepine Scaffold

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SYSNO ASEP	0385940
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	Structure-Aided Design of Novel Inhibitors of HIV Protease Based on a Benzodiazepine Scaffold
Author(s)	Schimer, Jiří (UOCHB-X)_{RID, ORCID} Cígler, Petr (UOCHB-X)_{RID, ORCID} Veselý, J. (CZ) Grantz Šašková, Klára (UOCHB-X)_{RID, ORCID} Lepšík, Martin (UOCHB-X)_{RID, ORCID} Brynda, Jiří (UMG-J)_RID Řezáčová, Pavlína (UOCHB-X)_{RID, ORCID} Kožíšek, Milan (UOCHB-X)_{RID, ORCID} Císařová, I. (CZ) Oberwinkler, H. (DE) Kraeusslich, H. G. (DE) Konvalinka, Jan (UOCHB-X)_{RID, ORCID}
Number of authors	12
Source Title	Journal of Medicinal Chemistry. - : American Chemical Society - ISSN 0022-2623 Roč. 55, č. 22 (2012), s. 10130-10135
Number of pages	6 s.
Language	eng - English
Country	US - United States
Keywords	HIV protease inhibitor ; rational drug design ; 1,4-benzodiazepines
Subject RIV	CE - Biochemistry
R&D Projects	GBP208/12/G016 GA ČR - Czech Science Foundation (CSF)
	GAP207/11/1798 GA ČR - Czech Science Foundation (CSF)
CEZ	AV0Z40550506 - UOCHB-X (2005-2011)
	AV0Z50520514 - UMG-J (2005-2011)
UT WOS	000311461500059
DOI	10.1021/jm301249q
Annotation	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.
Workplace	Institute of Organic Chemistry and Biochemistry
Contact	asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434
Year of Publishing	2013

Number of the records: 1