title: Identification of Novel D-Aspartate Oxidase Inhibitors by in Silico Screening and Their Functional and Structural Characterization in Vitro.
abstract: 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 μM). 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-function relationships of DDO.
authors: Laboratory of Biomolecular Science, Graduate School of Pharmaceutical and Life Sciences, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors: Masumi
authors: M
authors: Katane
authors: Laboratory of Biomolecular Science, Graduate School of Pharmaceutical and Life Sciences, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors: Shota
authors: S
authors: Yamada
authors: Laboratory of Biomolecular Science, Graduate School of Pharmaceutical and Life Sciences, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors: Go
authors: G
authors: Kawaguchi
authors: Laboratory of Biomolecular Science, Graduate School of Pharmaceutical and Life Sciences, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors: Mana
authors: M
authors: Chinen
authors: Laboratory of Biomolecular Science, Graduate School of Pharmaceutical and Life Sciences, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors: Maya
authors: M
authors: Matsumura
authors: Laboratory of Biomolecular Science, Graduate School of Pharmaceutical and Life Sciences, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors: Takemi
authors: T
authors: Ando
authors: Laboratory of Physical Chemistry for Drug Design, Graduate School of Pharmaceutical and Life Sciences, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors: Issei
authors: I
authors: Doi
authors: Laboratory of Biomolecular Science, Graduate School of Pharmaceutical and Life Sciences, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors: Kazuki
authors: K
authors: Nakayama
authors: Laboratory of Biomolecular Science, Graduate School of Pharmaceutical and Life Sciences, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors: Yuusuke
authors: Y
authors: Kaneko
authors: Laboratory of Biomolecular Science, Graduate School of Pharmaceutical and Life Sciences, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors: Satsuki
authors: S
authors: Matsuda
authors: Laboratory of Biomolecular Science, Graduate School of Pharmaceutical and Life Sciences, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors: Yasuaki
authors: Y
authors: Saitoh
authors: Laboratory of Biomolecular Science, Graduate School of Pharmaceutical and Life Sciences, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors: Tetsuya
authors: T
authors: Miyamoto
authors: Laboratory of Biomolecular Science, Graduate School of Pharmaceutical and Life Sciences, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors: Masae
authors: M
authors: Sekine
authors: Laboratory of Physical Chemistry for Drug Design, Graduate School of Pharmaceutical and Life Sciences, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors: Noriyuki
authors: N
authors: Yamaotsu
authors: Laboratory of Physical Chemistry for Drug Design, Graduate School of Pharmaceutical and Life Sciences, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors: Shuichi
authors: S
authors: Hirono
authors: Laboratory of Biomolecular Science, Graduate School of Pharmaceutical and Life Sciences, Kitasato University , 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors: Hiroshi
authors: H
authors: Homma
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D003198:Computer Simulation; D003605:D-Amino-Acid Oxidase / Q000037:antagonists & inhibitors; D050804:D-Aspartate Oxidase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D062126:Databases, Chemical; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009539:Nicotinic Acids / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C000603796:5-aminonicotinic acid; D009539:Nicotinic Acids; D011994:Recombinant Proteins; D050804:D-Aspartate Oxidase; C494102:DDO protein, human; D003605:D-Amino-Acid Oxidase