Structural, kinetic, and pharmacodynamic mechanisms of D-amino acid oxidase inhibition by small molecules

We characterized the mechanism and pharmacodynamics of five structurally distinct inhibitors of d-amino acid oxidase. All inhibitors bound the oxidized form of human enzyme with affinity slightly higher than that of benzoate (Kd ≈ 2-4 μM). Stopped-flow experiments showed that pyrrole-based inhibitor...

Celý popis

Uložené v:

Podrobná bibliografia
Vydané v:	Journal of medicinal chemistry Ročník 56; číslo 9; s. 3710
Hlavní autori:	Hopkins, Seth C, Heffernan, Michele L R, Saraswat, Lakshmi D, Bowen, Carrie A, Melnick, Laurence, Hardy, Larry W, Orsini, Michael A, Allen, Michael S, Koch, Patrick, Spear, Kerry L, Foglesong, Robert J, Soukri, Mustapha, Chytil, Milan, Fang, Q Kevin, Jones, Steven W, Varney, Mark A, Panatier, Aude, Oliet, Stephane H R, Pollegioni, Loredano, Piubelli, Luciano, Molla, Gianluca, Nardini, Marco, Large, Thomas H
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 09.05.2013
Predmet:	Animals Behavior, Animal - drug effects Binding, Competitive Catalytic Domain D-Amino-Acid Oxidase - antagonists & inhibitors D-Amino-Acid Oxidase - chemistry D-Amino-Acid Oxidase - metabolism Enzyme Inhibitors - chemistry Enzyme Inhibitors - metabolism Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - pharmacology Glycine - metabolism Humans Kinetics Male Molecular Docking Simulation Neuroglia - drug effects Neuroglia - metabolism Rats Rats, Sprague-Dawley Serine - biosynthesis Small Molecule Libraries - chemistry Small Molecule Libraries - metabolism Small Molecule Libraries - pharmacokinetics Small Molecule Libraries - pharmacology
ISSN:	1520-4804, 1520-4804
On-line prístup:	Zistit podrobnosti o prístupe
Tagy:	Pridať tag Žiadne tagy, Buďte prvý, kto otaguje tento záznam!

Popis
Shrnutí:	We characterized the mechanism and pharmacodynamics of five structurally distinct inhibitors of d-amino acid oxidase. All inhibitors bound the oxidized form of human enzyme with affinity slightly higher than that of benzoate (Kd ≈ 2-4 μM). Stopped-flow experiments showed that pyrrole-based inhibitors possessed high affinity (Kd ≈ 100-200 nM) and slow release kinetics (k < 0.01 s(-1)) in the presence of substrate, while inhibitors with pendent aromatic groups altered conformations of the active site lid, as evidenced by X-ray crystallography, and showed slower kinetics of association. Rigid bioisosteres of benzoic acid induced a closed-lid conformation, had slower release in the presence of substrate, and were more potent than benzoate. Steady-state d-serine concentrations were described in a PK/PD model, and competition for d-serine sites on NMDA receptors was demonstrated in vivo. DAAO inhibition increased the spatiotemporal influence of glial-derived d-serine, suggesting localized effects on neuronal circuits where DAAO can exert a neuromodulatory role.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1520-4804 1520-4804
DOI:	10.1021/jm4002583