title: Identification of novel D-amino acid oxidase inhibitors by in silico screening and their functional characterization in vitro.
abstract: 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-function relationships of DAO.
authors: Laboratory of Biomolecular Science, Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors: Masumi
authors: M
authors: Katane
authors: Naoko
authors: N
authors: Osaka
authors: Satsuki
authors: S
authors: Matsuda
authors: Kazuhiro
authors: K
authors: Maeda
authors: Tomonori
authors: T
authors: Kawata
authors: Yasuaki
authors: Y
authors: Saitoh
authors: Masae
authors: M
authors: Sekine
authors: Takemitsu
authors: T
authors: Furuchi
authors: Issei
authors: I
authors: Doi
authors: Shuichi
authors: S
authors: Hirono
authors: Hiroshi
authors: H
authors: Homma
mesh_terms: D014150:Antipsychotic Agents; D003198:Computer Simulation; D003605:D-Amino-Acid Oxidase / Q000037:antagonists & inhibitors*; D050804:D-Aspartate Oxidase / Q000037:antagonists & inhibitors; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000302:isolation & purification*; D006801:Humans; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D000099300:Serine Racemase
chemical_list: D014150:Antipsychotic Agents; D003605:D-Amino-Acid Oxidase; D050804:D-Aspartate Oxidase; D004791:Enzyme Inhibitors; D019998:Racemases and Epimerases; D000099300:Serine Racemase; C494102:DDO protein, human