Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan.
School of Pharmacy, Fudan University, Shanghai 201203, China.
Cell Chem Biol. 2020 Jun 18;27(6):708-718.e10. doi: 10.1016/j.chembiol.2020.04.007. Epub 2020 May 12.
Pharmacophore-focused chemical libraries are continuously being created in drug discovery programs, yet screening assays to maximize the usage of such libraries are not fully explored. Here, we report a chemical proteomics approach to reutilizing a focused chemical library of 1,800 indole-containing molecules for discovering uncharacterized ligand-protein pairs. Gel-based protein profiling of the library using a photo-affinity indole probe 1 enabled us to find new ligands for glyoxalase 1 (Glo1), an enzyme involved in the detoxification of methylglyoxal. Structure optimization of the ligands yielded an inhibitor for Glo1 (9). Molecule 9 increased the cellular methylglyoxal levels in human cells and suppressed the osteoclast formation of mouse bone marrow-derived macrophages. X-ray structure analyses revealed that the molecule lies at a site abutting the substrate binding site, which is consistent with the enzyme kinetic profile of 9. Overall, this study exemplifies how chemical proteomics can be used to exploit existing focused chemical libraries.
药物发现项目中不断创建基于药效团的化学文库，但尚未充分探索最大限度利用此类文库的筛选方法。在这里，我们报告了一种化学蛋白质组学方法，用于重新利用包含 1800 个吲哚的聚焦化学文库，以发现未表征的配体-蛋白对。使用光亲和吲哚探针 1 对文库进行凝胶基蛋白谱分析，使我们能够找到与参与甲基乙二醛解毒的酶-醛糖酶 1（Glo1）结合的新配体。配体的结构优化得到了 Glo1 的抑制剂（9）。分子 9 增加了人细胞中的甲基乙二醛水平，并抑制了小鼠骨髓来源的巨噬细胞中的破骨细胞形成。X 射线结构分析表明，该分子位于毗邻底物结合位点的位置，与 9 的酶动力学特征一致。总体而言，这项研究例证了化学蛋白质组学如何用于开发现有的聚焦化学文库。
