In silico and pharmacological screenings identify novel serine racemase inhibitors.
In silico and pharmacological screenings identify novel serine racemase inhibitors.
复制标题
通过计算机和药理学筛选鉴定出新型丝氨酸消旋酶抑制剂。
DOI：
10.1016/j.bmcl.2014.07.003
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发表时间：
2014
影响因子：
2.7
通讯作者：
Naoki Toyooka.
中科院分区：
文献类型：
--
作者：
Hisashi Mori;Ryogo Wada;Jie Li;Tetsuya Ishimoto;Mineyuki Mizuguchi;Takayuki Obita;Hiroaki Gouda;Shuichi Hirono;Naoki Toyooka.
D-丝氨酸是N-甲基-D-天冬氨酸(NMDA型)型谷氨酸受体的共激动剂，其生物合成由丝氨酸消旋酶(SR)催化。NMDA受体的过度激活与神经退行性疾病、中风和癫痫发作的发生有关，因此，SR的抑制剂具有潜在的抗这些病理状态的作用。在这里，我们通过电子筛选和体外酶试验开发了新型的SR抑制剂。与标准SR抑制剂之一丙二酸相比，新开发的抑制剂具有较低的IC50值。新型抑制剂的结构特征表明，其结构中含有苯氧基的中心酰胺结构对SR抑制活性具有重要意义。本研究结果提示了NMDAR过度激活疾病新药开发的重要性和合理性。
d-Serine is a coagonist of theN-methyl-d-aspartate (NMDA)-type glutamate receptor and its biosynthesis is catalyzed by serine racemase (SR). The overactivation of the NMDA receptor has been implicated in the development of neurodegenerative diseases, strokes, and epileptic seizures, thus, the inhibitors of SR have potential against these pathological states. Here, we have developed novel inhibitors of SR by in silico screening and in vitro enzyme assay. The newly developed inhibitors have lower IC50value comparing with that of malonate, one of the standard SR inhibitor. The structural features of novel inhibitors suggest the importance of central amide structure having a phenoxy substituent in their structure for the SR inhibitory activity. The present findings suggest the importance and rational development of new drugs for diseases of NMDAR overactivation.