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Structure-Based Reactivity Profiles of Reactive Metabolites with Glutathione.
Chemical Research in Toxicology ( IF 4.1 ) Pub Date : 2020-04-29 , DOI: 10.1021/acs.chemrestox.0c00081
Xiaomei Liu 1 , Hong Lv 1 , Yaqing Guo 1 , Tekleab Teka 1 , Xiaoming Wang 1 , Yuhong Huang 2 , Lifeng Han 1 , Guixiang Pan 2
Affiliation  

Therapeutic agents can be transformed into reactive metabolites under the action of various metabolic enzymes in vivo and then covalently combine with biological macromolecules (such as protein or DNA), resulting in increasing toxicity. The screening of reactive metabolites in drug discovery and development stages and monitoring of biotransformation in post-market drugs has become an important research field. Generally, reactive metabolites are electrophilic and can be captured by small nucleophiles. Glutathione (GSH) is a small peptide composed of three amino acids (i.e., glutamic acid, cysteine, and glycine). It has a thiol group which can react with electrophilic groups of reactive metabolic intermediates (such as benzoquinone, N-acetyl-p-benzoquinoneimine, and Michael acceptor) to form a stable binding conjugate. This paper aims to provide a review on structure-based reactivity profiles of reactive metabolites with GSH. Furthermore, this review also reveals the relationship between drugs’ molecular structures and reactive metabolic toxicity from the perspective of metabolism, giving a reference for drug design and development.

中文翻译:

反应性代谢物与谷胱甘肽的基于结构的反应性曲线。

治疗药物在体内各种代谢酶的作用下可转化为反应性代谢产物,然后与生物大分子(如蛋白质或DNA)共价结合,导致毒性增加。药物发现和开发阶段反应性代谢物的筛选以及上市后药物生物转化的监测已成为一个重要的研究领域。通常,反应性代谢物是亲电子的,可以被小的亲核试剂捕获。谷胱甘肽 (GSH) 是由三种氨基酸(即谷氨酸、半胱氨酸和甘氨酸)组成的小肽。具有硫醇基团,可与反应性代谢中间体(如苯醌、N-乙酰基-p-苯醌亚胺和迈克尔受体)形成稳定的结合缀合物。本文旨在对 GSH 的反应性代谢物的基于结构的反应性概况进行综述。此外,该综述还从代谢的角度揭示了药物分子结构与反应性代谢毒性之间的关系,为药物设计和开发提供参考。
更新日期:2020-04-29
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