Elucidation of inhibitor-binding pockets of D-amino acid oxidase using docking simulation and N-sulfanylethylanilide-based labeling technology

Because of relevance of D-serine (D-Ser) to schizophrenia, inhibitors of D-amino acid oxidase (DAO), which catalyzes degradation of D-Ser in the presence of flavin adeninde dinucleotide (FAD), are expected as anti-schizophrenia therapeutics. In this study, binding pockets of DAO to its inhibitor 4-bromo-3-nitrobenzoic acid were searched by combining in silico docking simulation and labeling experiments employing an N-sulfanylethylanilide-based labeling technology we have developed. The results clearly demonstrated that there are two binding pockets: one is shared with D-Ser and FAD, and the other is an unexpected cleft between subunits of a DAO dimer. These findings will provide insight to aid the development of new hDAO inhibitors. In addition, it was also proved that our labeling technology could be applicable to elucidate the binding pockets of proteins.

© The Royal Society of Chemistry 2017