Ehrler Johanna H M, Brunst Steffen, Tjaden Amelie, Kilu Whitney, Heering Jan, Hernandez-Olmos Victor, Krommes Andre, Kramer Jan S, Steinhilber Dieter, Schubert-Zsilavecz Manfred, Müller Susanne, Merk Daniel, Proschak Ewgenij
Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, D-60596 Frankfurt, Germany.
Biochem Pharmacol. 2022 Oct;204:115191. doi: 10.1016/j.bcp.2022.115191. Epub 2022 Jul 27.
Focused compound libraries are well-established tools for hit identification in drug discovery and chemical probe development. We present the compilation and application of a focused screening library of fatty acid mimetics (FAMs), which are compounds designed to bind the orthosteric site of proteins that endogenously accommodate natural fatty acids and lipid metabolites. This set complies with chemical properties of FAM and was found suitable for use also in cellular setting. Several hits were retrieved in screening the focused library against diverse fatty acid binding targets including the enzymes soluble epoxide hydrolase (sEH) and leukotriene A4 hydrolase (LTA4H), the nuclear receptors peroxisome proliferator-activated receptor γ (PPARγ) and retinoid X receptor α (RXRα), the carrier proteins fatty acid binding protein 4 and 5 (FABP4 and FABP5), as well as the G-protein coupled receptors leukotriene B4 receptor 1 (BLT1) and free-fatty acid receptor 1 (FFAR1). Thus, the focused FAM library is suitable to obtain chemical starting matter for fatty acid binding proteins and provides a valuable extension to available screening collections.
聚焦化合物库是药物发现和化学探针开发中用于发现活性化合物的成熟工具。我们展示了脂肪酸模拟物（FAM）聚焦筛选库的汇编和应用，这些化合物旨在结合内源性容纳天然脂肪酸和脂质代谢物的蛋白质的正构位点。该集合符合FAM的化学性质，并被发现也适用于细胞环境。在用聚焦库针对多种脂肪酸结合靶点进行筛选时，获得了多个活性化合物，这些靶点包括可溶性环氧化物水解酶（sEH）和白三烯A4水解酶（LTA4H）等酶、过氧化物酶体增殖物激活受体γ（PPARγ）和视黄酸X受体α（RXRα）等核受体、脂肪酸结合蛋白4和5（FABP4和FABP5）等载体蛋白，以及G蛋白偶联受体白三烯B4受体1（BLT1）和游离脂肪酸受体1（FFAR1）。因此，聚焦FAM库适合用于获取脂肪酸结合蛋白的化学起始物质，并为现有的筛选文库提供了有价值的扩展。
