Gai Conghao, Zhang Ya, Zhang Shihao, Hu Xueyan, Song Yun-Qing, Zhuang Xiaoyu, Chai Xiaoyun, Zou Yan, Ge Guang-Bo, Zhao Qingjie
Organic Chemistry Group, College of Pharmacy, Naval Medical University, Shanghai, China.
Shanghai Frontiers Science Centre of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Front Chem. 2024 Dec 3;12:1504453. doi: 10.3389/fchem.2024.1504453. eCollection 2024.
Halogens favorably contributes to the drug potency and metabolic stability via electrostatic interactions. Herein, the halogen effects on the reactivity of the halogenated 2,2,2-trifluoroacetophenones as serine-targeting covalent warheads were investigated. Our results showed that introducing halogen atoms, especially Cl or Br, into the phenyl scaffold would influence the electron density around the ring, which led to different time-dependent inhibition response to the target serine hydrolase (hCES1A). Co-crystallography analysis not only verified that halogenated molecules preferred to form covalent adducts, but also provided the conformational information for the design of covalent inhibitors targeting to hCES1A protein for the treatment of drug-induced acute enteritis.
卤素通过静电相互作用对药物效力和代谢稳定性有积极贡献。在此，研究了卤素对卤代2,2,2-三氟苯乙酮作为靶向丝氨酸的共价弹头反应性的影响。我们的结果表明，在苯基支架中引入卤素原子，尤其是Cl或Br，会影响环周围的电子密度，这导致对目标丝氨酸水解酶（hCES1A）产生不同的时间依赖性抑制反应。共结晶分析不仅证实卤代分子更倾向于形成共价加合物，还为设计靶向hCES1A蛋白以治疗药物性急性肠炎的共价抑制剂提供了构象信息。
