8GYD

Structure of Schistosoma japonicum Glutathione S-transferase bound with the ligand complex of 16

Summary for 8GYD

• Entry DOI: 10.2210/pdb8gyd/pdb
• Descriptor: Glutathione S-transferase class-mu 26 kDa isozyme, (2R)-2-[[2-(5-chloranylthiophen-2-yl)-4-oxidanylidene-6-[2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]quinazolin-3-yl]methyl]-3-(4-chlorophenyl)propanoic acid, ETHANOL, ... (4 entities in total)
• Functional Keywords: complex, transferase
• Biological source: Schistosoma japonicum (Blood fluke)
• Total number of polymer chains: 2
• Total formula weight: 56766.40

Authors

Wen, X.,Jin, R.,Hu, H.,Zhu, J.,Song, W.,Lu, X. (deposition date: 2022-09-22, release date: 2023-08-23, Last modification date: 2023-09-13)

Primary citation

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(1 H )-one Focused DNA-Encoded Library.
J.Med.Chem., 66:11118-11132, 2023

PubMed Abstract: 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(3)-one developed by a robust DNA-compatible multicomponent reaction and a series of novel glutathione -transferase (GST) inhibitors that were identified through affinity-mediated DEL selection. A novel inhibitor was subsequently verified with an inhibitory potency value of 1.55 ± 0.02 μM against SjGST and 2.02 ± 0.20 μM against hGSTM2. Further optimization was carried out via various structure-activity relationship studies. And especially, the co-crystal structure of the compound 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.

PubMed: 37552553
DOI: 10.1021/acs.jmedchem.2c02129

Experimental method

X-RAY DIFFRACTION (1.7 Å)