ACS Publications. Most Trusted. Most Cited. Most Read
My Activity

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

View Author Information
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
Copyright © 2013 American Chemical Society

    Article Views





    Other access options
    Supporting Info (1)»


    Abstract Image

    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.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.


    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

    Supporting Information

    Jump To

    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

    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system:

    Cited By

    This article is cited by 30 publications.

    1. Wei Liu, Jingsheng Jiang, Yating Lin, Qidong You, Lei Wang. Insight into Thermodynamic and Kinetic Profiles in Small-Molecule Optimization. Journal of Medicinal Chemistry 2022, 65 (16) , 10809-10847.
    2. Mattia Bernetti, Elena Rosini, Luca Mollica, Matteo Masetti, Loredano Pollegioni, Maurizio Recanatini, Andrea Cavalli. Binding Residence Time through Scaled Molecular Dynamics: A Prospective Application to hDAAO Inhibitors. Journal of Chemical Information and Modeling 2018, 58 (11) , 2255-2265.
    3. Niyada Hin, Bridget Duvall, Dana Ferraris, Jesse Alt, Ajit G. Thomas, Rana Rais, Camilo Rojas, Ying Wu, Krystyna M. Wozniak, Barbara S. Slusher, and Takashi Tsukamoto . 6-Hydroxy-1,2,4-triazine-3,5(2H,4H)-dione Derivatives as Novel d-Amino Acid Oxidase Inhibitors. Journal of Medicinal Chemistry 2015, 58 (18) , 7258-7272.
    4. Sarah C. Zimmermann, Rana Rais, Jesse Alt, Caitlin Burzynski, Barbara S. Slusher, and Takashi Tsukamoto . Structure–Metabolism Relationships in the Glucuronidation of d-Amino Acid Oxidase Inhibitors. ACS Medicinal Chemistry Letters 2014, 5 (11) , 1251-1253.
    5. Stefan G. Koenig, John W. Dankwardt, Yanbing Liu, Hang Zhao, and Surendra P. Singh . Copper-Catalyzed Synthesis of Indoles and Related Heterocycles in Renewable Solvents. ACS Sustainable Chemistry & Engineering 2014, 2 (6) , 1359-1363.
    6. Hang Zhao, Stefan G. Koenig, John W. Dankwardt, and Surendra P. Singh . Practical Nonazide Synthesis of a d-Amino Acid Oxidase Inhibitor via a Sequential Erlenmeyer–Plöchl Reaction and Ligand-Free Copper(I) Amination Protocol. Organic Process Research & Development 2014, 18 (1) , 198-204.
    7. Naushaba Hasin, Lace M. Riggs, Tatyana Shekhtman, Justin Ashworth, Robert Lease, Rediet T. Oshone, Elizabeth M. Humphries, Judith A. Badner, Pippa A. Thomson, David C. Glahn, David W. Craig, Howard J. Edenberg, Elliot S. Gershon, Francis J. McMahon, John I. Nurnberger, Peter P. Zandi, John R. Kelsoe, Jared C. Roach, Todd D. Gould, Seth A. Ament. Rare variants implicate NMDA receptor signaling and cerebellar gene networks in risk for bipolar disorder. Molecular Psychiatry 2022, 27 (9) , 3842-3856.
    8. Ju-Chun Pei, Da-Zhong Luo, Shiang-Shin Gau, Chia-Yuan Chang, Wen-Sung Lai. Directly and Indirectly Targeting the Glycine Modulatory Site to Modulate NMDA Receptor Function to Address Unmet Medical Needs of Patients With Schizophrenia. Frontiers in Psychiatry 2021, 12
    9. Katarina Kores, Janez Konc, Urban Bren. Mechanistic Insights into Side Effects of Troglitazone and Rosiglitazone Using a Novel Inverse Molecular Docking Protocol. Pharmaceutics 2021, 13 (3) , 315.
    10. . References. 2021, 243-287.
    11. Hannu Myllykallio, Hubert F. Becker, Alexey Aleksandrov. Mechanism of Naphthoquinone Selectivity of Thymidylate Synthase ThyX. Biophysical Journal 2020, 119 (12) , 2508-2516.
    12. Seiji Taniguchi, Haik Chosrowjan, Shoji Ito, Hiroshi Miyasaka, Masumi Katane, Hiroshi Homma, Fumio Tanaka, Arthit Nueangaudom, Kiattisak Lugsanangarm, Sirirat Kokpol. Comparative studies on picosecond-resolved fluorescence of d-amino acid oxidases from human with one from porcine kidney. Photoinduced electron transfer from aromatic amino acids to the excited flavin. Journal of Photochemistry and Photobiology B: Biology 2019, 198 , 111546.
    13. Bence Szilágyi, Csilla Hargitai, Ádám A. Kelemen, Anita Rácz, György G. Ferenczy, Balázs Volk, György M. Keserű. Synthesis and Biochemical Evaluation of Lid-Open D-Amino Acid Oxidase Inhibitors. Molecules 2019, 24 (2) , 290.
    14. Yusuke Kato, Niyada Hin, Nobuo Maita, Ajit G. Thomas, Sumire Kurosawa, Camilo Rojas, Kazuko Yorita, Barbara S. Slusher, Kiyoshi Fukui, Takashi Tsukamoto. Structural basis for potent inhibition of d-amino acid oxidase by thiophene carboxylic acids. European Journal of Medicinal Chemistry 2018, 159 , 23-34.
    15. Bence Szilágyi, György G. Ferenczy, György M. Keserű. Drug discovery strategies and the preclinical development of D-amino-acid oxidase inhibitors as antipsychotic therapies. Expert Opinion on Drug Discovery 2018, 13 (10) , 973-982.
    16. Giulia Murtas, Laura Caldinelli, Pamela Cappelletti, Silvia Sacchi, Loredano Pollegioni. Human d -amino acid oxidase: The inactive G183R variant. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 2018, 1866 (7) , 822-830.
    17. Kalyanasundaram Subramanian, Artur Góra, Ruud Spruijt, Karolina Mitusińska, Maria Suarez-Diez, Vitor Martins dos Santos, Peter J. Schaap, . Modulating D-amino acid oxidase (DAAO) substrate specificity through facilitated solvent access. PLOS ONE 2018, 13 (6) , e0198990.
    18. Zoltán Orgován, György G. Ferenczy, Thomas Steinbrecher, Bence Szilágyi, Dávid Bajusz, György M. Keserű. 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. Journal of Computer-Aided Molecular Design 2018, 32 (2) , 331-345.
    19. Elena Rosini, Laura Caldinelli, Luciano Piubelli. Assays of D-Amino Acid Oxidase Activity. Frontiers in Molecular Biosciences 2018, 4
    20. Reiko Koga, Yurika Miyoshi, Hiroaki Sakaue, Kenji Hamase, Ryuichi Konno. Mouse d-Amino-Acid Oxidase: Distribution and Physiological Substrates. Frontiers in Molecular Biosciences 2017, 4
    21. Gianluca Molla. Competitive Inhibitors Unveil Structure/Function Relationships in Human D-Amino Acid Oxidase. Frontiers in Molecular Biosciences 2017, 4
    22. Silvia Sacchi, Vito De Novellis, Giovanna Paolone, Tommaso Nuzzo, Monica Iannotta, Carmela Belardo, Marta Squillace, Paolo Bolognesi, Elena Rosini, Zoraide Motta, Martina Frassineti, Alessandro Bertolino, Loredano Pollegioni, Michele Morari, Sabatino Maione, Francesco Errico, Alessandro Usiello. Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity. Scientific Reports 2017, 7 (1)
    23. Taiki Kohiki, Yusuke Kato, Yusuke Nishikawa, Kazuko Yorita, Ikuko Sagawa, Masaya Denda, Tsubasa Inokuma, Akira Shigenaga, Kiyoshi Fukui, Akira Otaka. Elucidation of inhibitor-binding pockets of d -amino acid oxidase using docking simulation and N-sulfanylethylanilide-based labeling technology. Organic & Biomolecular Chemistry 2017, 15 (25) , 5289-5297.
    24. Niyada Hin, Bridget Duvall, James F. Berry, Dana V. Ferraris, Rana Rais, Jesse Alt, Camilo Rojas, Barbara S. Slusher, Takashi Tsukamoto. d-Amino acid oxidase inhibitors based on the 5-hydroxy-1,2,4-triazin-6(1H)-one scaffold. Bioorganic & Medicinal Chemistry Letters 2016, 26 (8) , 2088-2091.
    25. Jean-Pierre Mothet, Grégoire Mondielli, Magalie Martineau. Physiological Roles of d-Serine in the Central Nervous System. 2016, 27-50.
    26. Shohei Toguchi, Tomoyasu Hirose, Kazuko Yorita, Kiyoshi Fukui, K. Barry Sharpless, Satoshi Ōmura, Toshiaki Sunazuka. In Situ Click Chemistry for the Identification of a Potent D-Amino Acid Oxidase Inhibitor. CHEMICAL & PHARMACEUTICAL BULLETIN 2016, 64 (7) , 695-703.
    27. Pamela Cappelletti, Luciano Piubelli, Giulia Murtas, Laura Caldinelli, Mattia Valentino, Gianluca Molla, Loredano Pollegioni, Silvia Sacchi. Structure–function relationships in human d-amino acid oxidase variants corresponding to known SNPs. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 2015, 1854 (9) , 1150-1159.
    28. Shouji Takahashi, Makoto Furukawara, Keishi Omae, Namiho Tadokoro, Yayoi Saito, Katsumasa Abe, Yoshio Kera, . A Highly Stable d -Amino Acid Oxidase of the Thermophilic Bacterium Rubrobacter xylanophilus. Applied and Environmental Microbiology 2014, 80 (23) , 7219-7229.
    29. Dongsheng Xie, Yanchao Wang, Jin Xie, Jun Lu, Junjun Cui, Man Zhang, Lei Fu, Yongxiang Wang. Quinoxaline-2,3-diones: potential d-amino acid oxidase (DAAO) inhibitors. Medicinal Chemistry Research 2014, 23 (11) , 4977-4989.
    30. Ryan T. Terry-Lorenzo, Lawrence E. Chun, Scott P. Brown, Michele L. R. Heffernan, Q. Kevin Fang, Michael A. Orsini, Loredano Pollegioni, Larry W. Hardy, Kerry L. Spear, Thomas H. Large. Novel human D -amino acid oxidase inhibitors stabilize an active-site lid-open conformation. Bioscience Reports 2014, 34 (4)

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Your Mendeley pairing has expired. Please reconnect