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Publication Abstract from PubMed

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 approximately 2-4 muM). Stopped-flow experiments showed that pyrrole-based inhibitors possessed high affinity (Kd approximately 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.

Structural, Kinetic, and Pharmacodynamic Mechanisms of d-Amino Acid Oxidase Inhibition by Small Molecules.,Hopkins SC, Heffernan ML, Saraswat LD, Bowen CA, Melnick L, Hardy LW, Orsini MA, Allen MS, Koch P, Spear KL, Foglesong RJ, Soukri M, Chytil M, Fang QK, Jones SW, Varney MA, Panatier A, Oliet SH, Pollegioni L, Piubelli L, Molla G, Nardini M, Large TH J Med Chem. 2013 May 9;56(9):3710-24. doi: 10.1021/jm4002583. Epub 2013 Apr 30. PMID:23631755^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.