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Structural, Kinetic, and Pharmacodynamic Mechanisms of d-Amino Acid Oxidase Inhibition by Small Molecules

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Sunovion Pharmaceuticals Inc., Marlborough, Massachusetts 01752, United States
Neurocentre Magendie, Inserm U862 and Université de Bordeaux, Bordeaux, F-33077, France
§ Dipartimento di Biotecnologie e Scienze della Vita, Università degli Studi dell’Insubria, Via J. H. Dunant 3, 21100 Varese, Italy
The Protein Factory, Politecnico di Milano, ICRM-CNR and Università degli Studi dell’Insubria, Via Mancinelli 7, 20131 Milano, Italy
Tandem Labs, Durham, North Carolina, United States
# Scynexis, Durham, North Carolina, United States
Department of Biosciences, University of Milan, I-20133 Milano, Italy
*Phone: (508) 357-7706. Fax: (508) 490-5454. E-mail: [email protected]
Cite this: J. Med. Chem. 2013, 56, 9, 3710–3724
Publication Date (Web):April 30, 2013
https://doi.org/10.1021/jm4002583
Copyright © 2013 American Chemical Society

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    Abstract

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    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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    Table S1 listing X-ray data and processing statistics; derivation of in vivo d-serine concentration as a function of inhibitor concentration (eqs 4a, 4b, and 5). This material is available free of charge via the Internet at http://pubs.acs.org.

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