Identification\nof Novel d‑Aspartate Oxidase Inhibitors by <i>in Silico</i> Screening and Their Functional\nand Structural Characterization <i>in Vitro</i>

Abstract

d-Aspartate oxidase (DDO) is a degradative enzyme that\nis stereospecific for acidic d-amino acids, including d-aspartate, a potential agonist of the <i>N</i>-methyl-d-aspartate (NMDA) receptor. Dysfunction of NMDA receptor-mediated\nneurotransmission has been implicated in the onset of various mental\ndisorders, such as schizophrenia. Hence, a DDO inhibitor that increases\nthe brain levels of d-aspartate and thereby activates NMDA\nreceptor function is expected to be a useful compound. To search for\npotent DDO inhibitor(s), a large number of compounds were screened <i>in silico</i>, and several compounds were identified as candidates.\nThey were then characterized and evaluated as novel DDO inhibitors <i>in vitro</i> (e.g., the inhibitor constant value of 5-aminonicotinic\nacid for human DDO was 3.80 μM). The present results indicate\nthat some of these compounds may serve as lead compounds for the development\nof a clinically useful DDO inhibitor and as active site probes to\nelucidate the structure–function relationships of DDO.