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...

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Bibliographic Details
Published in:Journal of medicinal chemistry Vol. 56; no. 9; p. 3710
Main Authors: 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
Format: Journal Article
Language:English
Published: United States 09.05.2013
Subjects:
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
Online Access:Get more information
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Summary: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.
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ISSN:1520-4804
1520-4804
DOI:10.1021/jm4002583