Discovery of the first dual inhibitor of the 5-lipoxygenase-activating protein and soluble epoxide hydrolase using pharmacophore-based virtual screening.
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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DOI：
10.1038/srep42751
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发表时间：
2017-02-20
影响因子：
4.6
通讯作者：
Schuster D
中科院分区：
文献类型：
--
作者：
Temml V;Garscha U;Romp E;Schubert G;Gerstmeier J;Kutil Z;Matuszczak B;Waltenberger B;Stuppner H;Werz O;Schuster D
白三烯 (LT) 是源自花生四烯酸 (AA) 的促炎脂质介质，在炎症和过敏性疾病中发挥作用。 LT 的生物合成是通过 5-脂氧合酶激活蛋白 (FLAP) 将 AA 转移至 5-脂氧合酶 (5-LO) 来启动的。 FLAP 抑制消除 LT 形成，发挥抗炎作用。可溶性环氧化物水解酶 (sEH) 将 AA 衍生的抗炎环氧二十碳三烯酸 (EET) 转化为二羟基二十碳四烯酸 (di-HETE)。因此，它的抑制作用也可以抵抗炎症。使用 FLAP 和 sEH 双重抑制剂靶向 LT 生物合成和 EET 转化可能代表一种新颖、强大的抗炎策略。我们提出了一项基于药效团的虚拟筛选活动，筛选出 20 种命中化合物，其中 4 种靶向 FLAP，4 种是 sEH 抑制剂。其中，第一个针对 sEH 和 FLAP 的双重抑制剂被鉴定为 N-[4-(苯并噻唑-2-基甲氧基)-2-甲基苯基]-N’-(3,4-二氯苯基)脲，在基于细胞的 FLAP 测试系统中的 IC50 值为 200nM，在无细胞测定中 sEH 活性的 IC50 值为 20nM。
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 (di-HETEs). 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.