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

Abstract

Because of the 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 adenine dinucleotide (FAD), are expected to be 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 that 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 the subunits of a DAO dimer. These findings will provide insight to aid the development of new DAO inhibitors. In addition, it was also proved that our labeling technology could be applicable to elucidate the binding pockets of proteins.

• Authors: Taiki Kohiki, Yusuke Kato, Yusuke Nishikawa, Kazuko Yorita, Ikuko Sagawa, Masaya Denda, Tsubasa Inokuma, Akira Shigenaga, Kiyoshi Fukui, Akira Otaka
• Journal: Organic & biomolecular chemistry (Org Biomol Chem) Vol. 15 Issue 25 Pg. 5289-5297 (Jun 27 2017) ISSN: 1477-0539 [Electronic] England
• PMID: 28509930 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• Sulfur Compounds
• DAO protein, human
• D-Amino-Acid Oxidase

Topics

• Binding Sites (drug effects)
• D-Amino-Acid Oxidase (antagonists & inhibitors, chemistry, metabolism)
• Enzyme Inhibitors (chemistry, pharmacology)
• Humans
• Molecular Docking Simulation
• Molecular Structure
• Staining and Labeling
• Sulfur Compounds (chemistry)