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

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• 作者：Masumi Katane ; Naoko Osaka ; Satsuki Matsuda ; Kazuhiro Maeda ; Tomonori Kawata ; Yasuaki Saitoh ; Masae Sekine ; Takemitsu Furuchi ; Issei Doi ; Shuichi Hirono ; Hiroshi Homma
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 14, 2013
• 年：2013
• 卷：56
• 期：5
• 页码：1894-1907
• 全文大小：659K
• 年卷期：v.56,no.5(March 14, 2013)
• ISSN：1520-4804

文摘

d-Amino acid oxidase (DAO) is a degradative enzyme that is stereospecific for d-amino acids, including d-serine and d-alanine, which are potential coagonists 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 DAO inhibitor that augments the brain levels of d-serine and/or d-alanine and thereby activates NMDA receptor function is expected to be an antipsychotic drug, for instance, in the treatment of schizophrenia. In the search for potent DAO inhibitor(s), a large number of compounds were screened in silico, and several compounds were estimated as candidates. These compounds were then characterized and evaluated as novel DAO inhibitors in vitro. The results reported in this study indicate that some of these compounds are possible lead compounds for the development of a clinically useful DAO inhibitor and have the potential to serve as active site probes to elucidate the structure鈥揻unction relationships of DAO.