丝氨酸消旋酶激动剂的计算机模拟和体外筛选及其对阿尔茨海默病的体内疗效
In Silico and In Vitro Screening of Serine Racemase Agonist and In Vivo Efficacy on Alzheimer's Disease .
作者信息
Lu Chih-Hao, Chang Hao-Teng, Hsu Lee-Fen, Lee Ming-Hsueh, Cheng Jack, Wu Dong Chuan, Lin Wei-Yong
机构信息
Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 300093, Taiwan.
Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300093, Taiwan.
出版信息
Pharmaceuticals (Basel). 2023 Feb 13;16(2):280. doi: 10.3390/ph16020280.
The NMDA receptor hypofunction has been implicated in schizophrenia, memory impairment, and Alzheimer's disease. Modulating the abundance of D-serine, a co-agonist of the NMDA receptor, is a strategy to treat symptoms of the NMDA receptor hypofunction. In contrast to D-amino acid oxidase (DAAO) inhibitors, which aim at decreasing the loss of D-serine, this study tried to identify serine racemase (SRR) agonists, which boost the conversion of L-serine to D-serine. We used holo and apo structures of human SRR for the molecular docking against the National Cancer Institute (NCI) and ZINC compound databases and validated their efficacy by in vitro SRR activity assay. We identified NSC294149 (2-amino-3-(3-nitroimidazo[1,2-a]pyridin-2-yl)sulfanylpropanoic acid) as a potential SRR agonist and confirmed its amelioration of the hazard ratio of survival of the AD model of fruit fly (). These results suggest that the SRR agonist could be a drug design target against the NMDA receptor hypofunction symptoms.
N-甲基-D-天冬氨酸受体功能减退与精神分裂症、记忆障碍和阿尔茨海默病有关。调节N-甲基-D-天冬氨酸受体的共激动剂D-丝氨酸的丰度是治疗N-甲基-D-天冬氨酸受体功能减退症状的一种策略。与旨在减少D-丝氨酸损失的D-氨基酸氧化酶（DAAO）抑制剂不同，本研究试图鉴定丝氨酸消旋酶（SRR）激动剂，其可促进L-丝氨酸向D-丝氨酸的转化。我们利用人SRR的全酶和脱辅基结构与美国国立癌症研究所（NCI）和ZINC化合物数据库进行分子对接，并通过体外SRR活性测定验证其功效。我们鉴定出NSC294149（2-氨基-3-（3-硝基咪唑并[1,2-a]吡啶-2-基）硫烷基丙酸）作为一种潜在的SRR激动剂，并证实其改善了果蝇AD模型的生存风险比（）。这些结果表明，SRR激动剂可能是针对N-甲基-D-天冬氨酸受体功能减退症状的药物设计靶点。
Zotero 插件