4 research outputs found
Structure of the complex of porcine pancreatic elastase with a trimacrocyclic peptide inhibitor FR901451
The crystal structure of porcine pancreatic elastase complexed with a novel trimacrocyclic peptide inhibitor FR901451 was solved at 1.9 Å resolution
Structure of a high-resolution crystal form of human triosephosphate isomerase: improvement of crystals using the gel-tube method
A high-resolution structure of human triosephosphate isomerase was obtained from crystals improved by means of the gel-tube method
Inhibitor-induced structural change of the active site of human poly(ADP-ribose) polymerase
4‑Hydroxypyridazin-3(2<i>H</i>)‑one Derivatives as Novel d‑Amino Acid Oxidase Inhibitors
d-Amino acid oxidase (DAAO) catalyzes the oxidation of d-amino acids including d-serine, a coagonist of the <i>N</i>-methyl-d-aspartate receptor. We identified a
series of 4-hydroxypyridazin-3Â(2<i>H</i>)-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-2Â(1<i>H</i>)-one, to fill this subpocket with the aid of complex structure
information. 3-Hydroxy-5-(2-phenylethyl)Âpyridine-2Â(1<i>H</i>)-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-3Â(2<i>H</i>)-one derivatives, which are equivalent to the 3-hydroxy-pyridine-2Â(1<i>H</i>)-one series but lack cell toxicity. 6-[2-(3,5-Difluorophenyl)Âethyl]-4-hydroxypyridazin-3Â(2<i>H</i>)-one was found to be effective against MK-801-induced
cognitive deficit in the Y-maze