7U9S
Crystal structure of human D-amino acid oxidase in complex with inhibitor
Summary for 7U9S
| Entry DOI | 10.2210/pdb7u9s/pdb |
| Descriptor | D-amino-acid oxidase, FLAVIN-ADENINE DINUCLEOTIDE, 5-{2-[4-(trifluoromethyl)phenyl]ethyl}-1,4-dihydropyrazine-2,3-dione, ... (4 entities in total) |
| Functional Keywords | fad, flavoprotein, oxidoreductase, peroxisome, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 81181.39 |
| Authors | Skene, R.J.,Bell, J.A. (deposition date: 2022-03-11, release date: 2022-06-08, Last modification date: 2023-10-18) |
| Primary citation | Tang, H.,Jensen, K.,Houang, E.,McRobb, F.M.,Bhat, S.,Svensson, M.,Bochevarov, A.,Day, T.,Dahlgren, M.K.,Bell, J.A.,Frye, L.,Skene, R.J.,Lewis, J.H.,Osborne, J.D.,Tierney, J.P.,Gordon, J.A.,Palomero, M.A.,Gallati, C.,Chapman, R.S.L.,Jones, D.R.,Hirst, K.L.,Sephton, M.,Chauhan, A.,Sharpe, A.,Tardia, P.,Dechaux, E.A.,Taylor, A.,Waddell, R.D.,Valentine, A.,Janssens, H.B.,Aziz, O.,Bloomfield, D.E.,Ladha, S.,Fraser, I.J.,Ellard, J.M. Discovery of a Novel Class of d-Amino Acid Oxidase Inhibitors Using the Schrodinger Computational Platform. J.Med.Chem., 65:6775-6802, 2022 Cited by PubMed Abstract: d-Serine is a coagonist of the -methyl d-aspartate (NMDA) receptor, a key excitatory neurotransmitter receptor. In the brain, d-serine is synthesized from its l-isomer by serine racemase and is metabolized by the D-amino acid oxidase (DAO, DAAO). Many studies have linked decreased d-serine concentration and/or increased DAO expression and enzyme activity to NMDA dysfunction and schizophrenia. Thus, it is feasible to employ DAO inhibitors for the treatment of schizophrenia and other indications. Powered by the Schrödinger computational modeling platform, we initiated a research program to identify novel DAO inhibitors with the best-in-class properties. The program execution leveraged an hDAO FEP+ model to prospectively predict compound potency. A new class of DAO inhibitors with desirable properties has been discovered from this endeavor. Our modeling technology on this program has not only enhanced the efficiency of structure-activity relationship development but also helped to identify a previously unexplored subpocket for further optimization. PubMed: 35482677DOI: 10.1021/acs.jmedchem.2c00118 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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