文献类型：期刊文献

英文题名：The discovery of novel small molecule allosteric activators of aldehyde dehydrogenase 2

作者：Tian, Wei[1,2];Guo, Jiapeng[1];Zhang, Qingsen[1];Fang, Shaoyu[1];Zhou, Ruolan[1];Hu, Jian[1];Wang, Mingping[1];Zhang, Yuefan[3];Guo, Jin-Min[4];Chen, Zhuo[5];Zhu, Ju[1];Zheng, Canhui[1]

机构：[1]Second Mil Med Univ, Sch Pharm, Shanghai 200433, Peoples R China;[2]Gen Hosp Cent Theater Commond, Wuhan 430070, Hubei, Peoples R China;[3]Shanghai Univ, Sch Med, Shanghai 20444, Peoples R China;[4]960 Hosp Joint Logist Support Force, Jinan 250031, Shandong, Peoples R China;[5]East China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China

年份：2021

卷号：212

外文期刊名：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000629622800022)】；

基金：This work was supported by Shanghai Pujiang Program (2019PJD058) and Shanghai Biological and Pharmaceutical Science and Technology Support Program (20S11903000).

语种：英文

外文关键词：Aldehyde dehydrogenase 2; Allosteric activators; Inactive Asian variant; Virtual screening; Structural optimization; Ischemic stroke

摘要：Aldehyde dehydrogenase 2 (ALDH2) plays important role in ethanol metabolism, and also serves as an important shield from the damage occurring under oxidative stress. A special inactive variant was found carried by 35-45% of East Asians. The variant carriers have recently been found at the higher risk for the diseases related to the damage occurring under oxidative stress, such as cardiovascular and cerebrovascular diseases. As a result, ALDH2 activators may potentially serve as a new class of therapeutics. Herein, N-benzylanilines were found as novel allosteric activators of ALDH2 by computational virtual screening using ligand-based and structure-based screening parallel screening strategy. Then a structural optimization was performed and has led to the discovery of the compound C6. It has good activity in vitro and in vivo, which could reduce infarct size by similar to 70% in ischemic stroke rat models. This study provided good lead compounds for the further development of ALDH2 activators. (C) 2020 Elsevier Masson SAS. All rights reserved.