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.

Structural, Kinetic, and Pharmacodynamic Mechanisms ofd-Amino Acid Oxidase Inhibition by Small Molecules / S.C. Hopkins, M.L.R. Heffernan, L.D. Saraswat, C.A. Bowen, L. Melnick, L.W. Hardy, M.A. Orsini, M.S. Allen, P. Koch, K.L. Spear, R.J. Foglesong, M. Soukri, M. Chytil, Q.K. Fang, S.W. Jones, M.A. Varney, A. Panatier, S.H.R. Oliet, L. Pollegioni, L. Piubelli, G. Molla, M. Nardini, T.H. Large. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 56:9(2013 May 09), pp. 3710-3724. [10.1021/jm4002583]

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

M. Nardini
Penultimo
;
2013

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.
D-ASPARTATE RECEPTOR ; NEUROMODULATOR D-SERINE ; LONG-TERM POTENTIATION ; INDUCED TONIC PAIN ; NMDA RECEPTORS ; MUTANT MICE ; GLYCINE SITE ; RAT-BRAIN ; NEURONAL MIGRATION ; VERTEBRATE RETINA
Settore BIO/10 - Biochimica
Settore BIO/14 - Farmacologia
Settore BIO/15 - Biologia Farmaceutica
9-mag-2013
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/223646
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