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Discovery of the first dual inhibitor of the 5-lipoxygenase-activating protein and soluble epoxide hydrolase using pharmacophore-based virtual screening
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SYSNO ASEP 0474823 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Discovery of the first dual inhibitor of the 5-lipoxygenase-activating protein and soluble epoxide hydrolase using pharmacophore-based virtual screening Author(s) Temml, V. (AT)
Garscha, U. (DE)
Romp, E. (DE)
Schubert, G. (DE)
Gerstmeier, J. (DE)
Kutil, Zsófia (UEB-Q)
Matuszczak, B. (AT)
Waltenberger, B. (AT)
Stuppner, H. (AT)
Werz, O. (DE)
Schuster, D. (AT)Number of authors 11 Article number 42751 Source Title Scientific Reports. - : Nature Publishing Group - ISSN 2045-2322
Roč. 7, FEB 20 (2017)Number of pages 8 s. Language eng - English Country GB - United Kingdom Keywords activating protein ; drug discovery ; leukotriene biosynthesis ; inflammatory diseases ; conformer generation ; arachidonic-acid ; flap ; challenges ; asthma ; risk Subject RIV CE - Biochemistry OECD category Physiology (including cytology) Institutional support UEB-Q - RVO:61389030 UT WOS 000394419900001 DOI 10.1038/srep42751 Annotation Leukotrienes (LTs) are pro-inflammatory lipid mediators derived from arachidonic acid (AA) with roles in inflammatory and allergic diseases. The biosynthesis of LTs is initiated by transfer of AA via the 5-lipoxygenase-activating protein (FLAP) to 5-lipoxygenase (5-LO). FLAP inhibition abolishes LT formation exerting anti-inflammatory effects. The soluble epoxide hydrolase (sEH) converts AA-derived anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatetraenoic acids (diHETEs). Its inhibition consequently also counteracts inflammation. Targeting both LT biosynthesis and the conversion of EETs with a dual inhibitor of FLAP and sEH may represent a novel, powerful anti-inflammatory strategy. We present a pharmacophore-based virtual screening campaign that led to 20 hit compounds of which 4 targeted FLAP and 4 were sEH inhibitors. Among them, the first dual inhibitor for sEH and FLAP was identified, N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]-N'-(3,4-dichlorophenyl) urea with IC50 values of 200 nM in a cell-based FLAP test system and 20 nM for sEH activity in a cell-free assay. Workplace Institute of Experimental Botany Contact David Klier, knihovna@ueb.cas.cz, Tel.: 220 390 469 Year of Publishing 2018
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