2020年6月
Chemoproteomic Profiling of a Pharmacophore-Focused Chemical Library
Cell Chemical Biology
- 巻
- 27
- 号
- 6
- 開始ページ
- 708
- 終了ページ
- 718.e10
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1016/j.chembiol.2020.04.007
- 出版者・発行元
- Elsevier BV
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.
- リンク情報
- ID情報
-
- DOI : 10.1016/j.chembiol.2020.04.007
- ISSN : 2451-9456
- PubMed ID : 32402240