3W4K

Crystal Structure of human DAAO in complex with coumpound 13

Summary for 3W4K

• Entry DOI: 10.2210/pdb3w4k/pdb
• Related: 3W4I 3W4J
• Descriptor: D-amino-acid oxidase, FLAVIN-ADENINE DINUCLEOTIDE, 3-hydroxy-6-(2-phenylethyl)pyridazin-4(1H)-one (3 entities in total)
• Functional Keywords: oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 162090.78

Authors

Hondo, T.,Warizaya, M.,Niimi, T.,Namatame, I.,Yamaguchi, T.,Nakanishi, K.,Hamajima, T.,Harada, K.,Sakashita, H.,Matsumoto, Y.,Orita, M.,Watanabe, T.,Takeuchi, M. (deposition date: 2013-01-09, release date: 2013-05-29, Last modification date: 2024-03-20)

Primary citation

Hondo, T.,Warizaya, M.,Niimi, T.,Namatame, I.,Yamaguchi, T.,Nakanishi, K.,Hamajima, T.,Harada, K.,Sakashita, H.,Matsumoto, Y.,Orita, M.,Takeuchi, M.
4-Hydroxypyridazin-3(2H)-one Derivatives as Novel d-Amino Acid Oxidase Inhibitors.
J.Med.Chem., 56:3582-3592, 2013

PubMed Abstract: D-Amino acid oxidase (DAAO) catalyzes the oxidation of d-amino acids including d-serine, a coagonist of the N-methyl-d-aspartate receptor. We identified a series of 4-hydroxypyridazin-3(2H)-one derivatives as novel DAAO inhibitors with high potency and substantial cell permeability using fragment-based drug design. Comparisons of complex structures deposited in the Protein Data Bank as well as those determined with in-house fragment hits revealed that a hydrophobic subpocket was formed perpendicular to the flavin ring by flipping Tyr224 in a ligand-dependent manner. We investigated the ability of the initial fragment hit, 3-hydroxy-pyridine-2(1H)-one, to fill this subpocket with the aid of complex structure information. 3-Hydroxy-5-(2-phenylethyl)pyridine-2(1H)-one exhibited the predicted binding mode and demonstrated high inhibitory activity for human DAAO in enzyme- and cell-based assays. We further designed and synthesized 4-hydroxypyridazin-3(2H)-one derivatives, which are equivalent to the 3-hydroxy-pyridine-2(1H)-one series but lack cell toxicity. 6-[2-(3,5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one was found to be effective against MK-801-induced cognitive deficit in the Y-maze.

PubMed: 23566269
DOI: 10.1021/jm400095b

Experimental method

X-RAY DIFFRACTION (2.86 Å)