化学
药物发现
DNA
谷胱甘肽
计算生物学
组合化学
转移酶
立体化学
化学图书馆
结构-活动关系
生物化学
酶
小分子
体外
生物
作者
Xin Wen,Minmin Zhang,Zhiqiang Duan,Yanrui Suo,Weiwei Lu,Rui Jin,Bokun Mu,Kaige Li,Zhijian Xu,Linghua Meng,Hong Yu,Xingyu Wang,Hangchen Hu,Jian-Yong Zhu,Weixiao Song,Aijun Shen,Xiaojie Lu
标识
DOI:10.1021/acs.jmedchem.2c02129
摘要
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 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 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.
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