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.
journal_name
Cell Chem Bioljournal_title
Cell chemical biologyauthors
Punzalan LL,Jiang L,Mao D,Mahapatra AD,Sato S,Takemoto Y,Tsujimura M,Kusamori K,Nishikawa M,Zhou L,Uesugi Mdoi
10.1016/j.chembiol.2020.04.007subject
Has Abstractpub_date
2020-06-18 00:00:00pages
708-718.e10issue
6eissn
2451-9456issn
2451-9448pii
S2451-9456(20)30144-6journal_volume
27pub_type
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