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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 56 3710-24 (2013)
Related entries: 3zno, 3znp, 3znq

Cited: 20 times
EuropePMC logo PMID: 23631755

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.

Reviews - 3znn mentioned but not cited (1)

  1. Competitive Inhibitors Unveil Structure/Function Relationships in Human D-Amino Acid Oxidase. Molla G. Front Mol Biosci 4 80 (2017)

Articles - 3znn mentioned but not cited (2)

  1. The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM. F1000Res 2 286 (2013)
  2. Structural basis for potent inhibition of d-amino acid oxidase by thiophene carboxylic acids. Kato Y, Hin N, Maita N, Thomas AG, Kurosawa S, Rojas C, Yorita K, Slusher BS, Fukui K, Tsukamoto T. Eur J Med Chem 159 23-34 (2018)


Reviews citing this publication (3)

  1. Mouse d-Amino-Acid Oxidase: Distribution and Physiological Substrates. Koga R, Miyoshi Y, Sakaue H, Hamase K, Konno R. Front Mol Biosci 4 82 (2017)
  2. Directly and Indirectly Targeting the Glycine Modulatory Site to Modulate NMDA Receptor Function to Address Unmet Medical Needs of Patients With Schizophrenia. Pei JC, Luo DZ, Gau SS, Chang CY, Lai WS. Front Psychiatry 12 742058 (2021)
  3. Drug discovery strategies and the preclinical development of D-amino-acid oxidase inhibitors as antipsychotic therapies. Szilágyi B, Ferenczy GG, Keserű GM. Expert Opin Drug Discov 13 973-982 (2018)

Articles citing this publication (14)

  1. Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity. Sacchi S, Novellis V, Paolone G, Nuzzo T, Iannotta M, Belardo C, Squillace M, Bolognesi P, Rosini E, Motta Z, Frassineti M, Bertolino A, Pollegioni L, Morari M, Maione S, Errico F, Usiello A. Sci Rep 7 46288 (2017)
  2. Novel human D-amino acid oxidase inhibitors stabilize an active-site lid-open conformation. Terry-Lorenzo RT, Chun LE, Brown SP, Heffernan ML, Fang QK, Orsini MA, Pollegioni L, Hardy LW, Spear KL, Large TH. Biosci Rep 34 e00133 (2014)
  3. A Highly Stable D-Amino Acid Oxidase of the Thermophilic Bacterium Rubrobacter xylanophilus. Takahashi S, Furukawara M, Omae K, Tadokoro N, Saito Y, Abe K, Kera Y. Appl Environ Microbiol 80 7219-7229 (2014)
  4. 6-Hydroxy-1,2,4-triazine-3,5(2H,4H)-dione Derivatives as Novel D-Amino Acid Oxidase Inhibitors. Hin N, Duvall B, Ferraris D, Alt J, Thomas AG, Rais R, Rojas C, Wu Y, Wozniak KM, Slusher BS, Tsukamoto T. J Med Chem 58 7258-7272 (2015)
  5. Mechanistic Insights into Side Effects of Troglitazone and Rosiglitazone Using a Novel Inverse Molecular Docking Protocol. Kores K, Konc J, Bren U. Pharmaceutics 13 315 (2021)
  6. Modulating D-amino acid oxidase (DAAO) substrate specificity through facilitated solvent access. Subramanian K, Góra A, Spruijt R, Mitusińska K, Suarez-Diez M, Martins Dos Santos V, Schaap PJ. PLoS One 13 e0198990 (2018)
  7. Assays of D-Amino Acid Oxidase Activity. Rosini E, Caldinelli L, Piubelli L. Front Mol Biosci 4 102 (2017)
  8. D-Amino acid oxidase inhibitors based on the 5-hydroxy-1,2,4-triazin-6(1H)-one scaffold. Hin N, Duvall B, Berry JF, Ferraris DV, Rais R, Alt J, Rojas C, Slusher BS, Tsukamoto T. Bioorg Med Chem Lett 26 2088-2091 (2016)
  9. Elucidation of inhibitor-binding pockets of d-amino acid oxidase using docking simulation and N-sulfanylethylanilide-based labeling technology. Kohiki T, Kato Y, Nishikawa Y, Yorita K, Sagawa I, Denda M, Inokuma T, Shigenaga A, Fukui K, Otaka A. Org Biomol Chem 15 5289-5297 (2017)
  10. Structure-Metabolism Relationships in the Glucuronidation of d-Amino Acid Oxidase Inhibitors. Zimmermann SC, Rais R, Alt J, Burzynski C, Slusher BS, Tsukamoto T. ACS Med Chem Lett 5 1251-1253 (2014)
  11. Rare variants implicate NMDA receptor signaling and cerebellar gene networks in risk for bipolar disorder. Hasin N, Riggs LM, Shekhtman T, Ashworth J, Lease R, Oshone RT, Humphries EM, Badner JA, Thomson PA, Glahn DC, Craig DW, Edenberg HJ, Gershon ES, McMahon FJ, Nurnberger JI, Zandi PP, Kelsoe JR, Roach JC, Gould TD, Ament SA. Mol Psychiatry 27 3842-3856 (2022)
  12. Validation of tautomeric and protomeric binding modes by free energy calculations. A case study for the structure based optimization of D-amino acid oxidase inhibitors. Orgován Z, Ferenczy GG, Steinbrecher T, Szilágyi B, Bajusz D, Keserű GM. J Comput Aided Mol Des 32 331-345 (2018)
  13. Mechanism of Naphthoquinone Selectivity of Thymidylate Synthase ThyX. Myllykallio H, Becker HF, Aleksandrov A. Biophys J 119 2508-2516 (2020)
  14. Synthesis and Biochemical Evaluation of Lid-Open D-Amino Acid Oxidase Inhibitors. Szilágyi B, Hargitai C, Kelemen ÁA, Rácz A, Ferenczy GG, Volk B, Keserű GM. Molecules 24 E290 (2019)


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