title: Structural, kinetic, and pharmacodynamic mechanisms of D-amino acid oxidase inhibition by small molecules.
abstract: 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.
authors: Sunovion Pharmaceuticals Inc., Marlborough, Massachusetts 01752, United States. seth.hopkins@sunovion.com
authors: Seth C
authors: SC
authors: Hopkins
authors: Michele L R
authors: ML
authors: Heffernan
authors: Lakshmi D
authors: LD
authors: Saraswat
authors: Carrie A
authors: CA
authors: Bowen
authors: Laurence
authors: L
authors: Melnick
authors: Larry W
authors: LW
authors: Hardy
authors: Michael A
authors: MA
authors: Orsini
authors: Michael S
authors: MS
authors: Allen
authors: Patrick
authors: P
authors: Koch
authors: Kerry L
authors: KL
authors: Spear
authors: Robert J
authors: RJ
authors: Foglesong
authors: Mustapha
authors: M
authors: Soukri
authors: Milan
authors: M
authors: Chytil
authors: Q Kevin
authors: QK
authors: Fang
authors: Steven W
authors: SW
authors: Jones
authors: Mark A
authors: MA
authors: Varney
authors: Aude
authors: A
authors: Panatier
authors: Stephane H R
authors: SH
authors: Oliet
authors: Loredano
authors: L
authors: Pollegioni
authors: Luciano
authors: L
authors: Piubelli
authors: Gianluca
authors: G
authors: Molla
authors: Marco
authors: M
authors: Nardini
authors: Thomas H
authors: TH
authors: Large
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive; D020134:Catalytic Domain; D003605:D-Amino-Acid Oxidase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D005998:Glycine / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008297:Male; D062105:Molecular Docking Simulation; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000096:biosynthesis; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D012694:Serine; D003605:D-Amino-Acid Oxidase; D005998:Glycine