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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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    0474823 - ÚEB 2018 RIV GB eng J - Journal Article
    Temml, V. - Garscha, U. - Romp, E. - Schubert, G. - Gerstmeier, J. - Kutil, Zsófia - Matuszczak, B. - Waltenberger, B. - Stuppner, H. - Werz, O. - Schuster, D.
    Discovery of the first dual inhibitor of the 5-lipoxygenase-activating protein and soluble epoxide hydrolase using pharmacophore-based virtual screening.
    Scientific Reports. Roč. 7, FEB 20 (2017), č. článku 42751. ISSN 2045-2322
    Institutional support: RVO:61389030
    Keywords : activating protein * drug discovery * leukotriene biosynthesis * inflammatory diseases * conformer generation * arachidonic-acid * flap * challenges * asthma * risk
    Subject RIV: CE - Biochemistry
    OBOR OECD: Physiology (including cytology)
    Impact factor: 4.122, year: 2017

    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.
    Permanent Link: http://hdl.handle.net/11104/0271773
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