Identification of Novel d-Aspartate Oxidase Inhibitors by in Silico Screening and Their Functional and Structural Characterization in Vitro

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• 作者：Masumi Katane ; Shota Yamada ; Go Kawaguchi ; Mana Chinen ; Maya Matsumura ; Takemi Ando ; Issei Doi ; Kazuki Nakayama ; Yuusuke Kaneko ; Satsuki Matsuda ; Yasuaki Saitoh ; Tetsuya Miyamoto ; Masae Sekine ; Noriyuki Yamaotsu ; Shuichi Hirono ; Hiroshi Homma
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：September 24, 2015
• 年：2015
• 卷：58
• 期：18
• 页码：7328-7340
• 全文大小：576K
• ISSN：1520-4804

文摘

d-Aspartate oxidase (DDO) is a degradative enzyme that is stereospecific for acidic d-amino acids, including d-aspartate, a potential agonist of the N-methyl-d-aspartate (NMDA) receptor. Dysfunction of NMDA receptor-mediated neurotransmission has been implicated in the onset of various mental disorders, such as schizophrenia. Hence, a DDO inhibitor that increases the brain levels of d-aspartate and thereby activates NMDA receptor function is expected to be a useful compound. To search for potent DDO inhibitor(s), a large number of compounds were screened in silico, and several compounds were identified as candidates. They were then characterized and evaluated as novel DDO inhibitors in vitro (e.g., the inhibitor constant value of 5-aminonicotinic acid for human DDO was 3.80 渭M). The present results indicate that some of these compounds may serve as lead compounds for the development of a clinically useful DDO inhibitor and as active site probes to elucidate the structure鈥揻unction relationships of DDO.