| RRC ID |
67014
|
| 著者 |
Punzalan LL, Jiang L, Mao D, Mahapatra AD, Sato S, Takemoto Y, Tsujimura M, Kusamori K, Nishikawa M, Zhou L, Uesugi M.
|
| タイトル |
Chemoproteomic Profiling of a Pharmacophore-Focused Chemical Library.
|
| ジャーナル |
Cell Chem Biol
|
| Abstract |
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.
|
| 巻・号 |
27(6)
|
| ページ |
708-718.e10
|
| 公開日 |
2020-6-18
|
| DOI |
10.1016/j.chembiol.2020.04.007
|
| PII |
S2451-9456(20)30144-6
|
| PMID |
32402240
|
| MeSH |
Animals
Cells, Cultured
Crystallography, X-Ray
Humans
Kinetics
Lactoylglutathione Lyase / antagonists & inhibitors*
Lactoylglutathione Lyase / metabolism
Ligands
Male
Mice
Mice, Inbred Strains
Models, Molecular
Molecular Structure
Proteomics*
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
|
| IF |
6.762
|
| リソース情報 |
| ヒト・動物細胞 |
293(RCB1637)
A549(RCB0098) |
