Structural highlights
Function
GST26_SCHJA Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. GST isoenzymes appear to play a central role in the parasite detoxification system. Other functions are also suspected including a role in increasing the solubility of haematin in the parasite gut.
Publication Abstract from PubMed
The DNA-encoded library (DEL) is a powerful hit-generation tool in drug discovery. This study describes a new DEL with a privileged scaffold quinazolin-4(3H)-one developed by a robust DNA-compatible multicomponent reaction and a series of novel glutathione S-transferase (GST) inhibitors that were identified through affinity-mediated DEL selection. A novel inhibitor 16 was subsequently verified with an inhibitory potency value of 1.55 +/- 0.02 muM against SjGST and 2.02 +/- 0.20 muM against hGSTM2. Further optimization was carried out via various structure-activity relationship studies. And especially, the co-crystal structure of the compound 16 with the SjGST was unveiled, which clearly demonstrated its binding mode was quite different from the known GSH-like compounds. This new type of probe is likely to play a different role compared with the GSH, which may provide new opportunities to discover more potent GST inhibitors.
Discovery, SAR Study of GST Inhibitors from a Novel Quinazolin-4(1H)-one Focused DNA-Encoded Library.,Wen X, Zhang M, Duan Z, Suo Y, Lu W, Jin R, Mu B, Li K, Zhang X, Meng L, Hong Y, Wang X, Hu H, Zhu J, Song W, Shen A, Lu X J Med Chem. 2023 Aug 8. doi: 10.1021/acs.jmedchem.2c02129. PMID:37552553[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wen X, Zhang M, Duan Z, Suo Y, Lu W, Jin R, Mu B, Li K, Zhang X, Meng L, Hong Y, Wang X, Hu H, Zhu J, Song W, Shen A, Lu X. Discovery, SAR Study of GST Inhibitors from a Novel Quinazolin-4(1H)-one Focused DNA-Encoded Library. J Med Chem. 2023 Aug 8. PMID:37552553 doi:10.1021/acs.jmedchem.2c02129
