7U9U

Crystal structure of human D-amino acid oxidase in complex with inhibitor

7U9U の概要

• エントリーDOI: 10.2210/pdb7u9u/pdb
• 分子名称: D-amino-acid oxidase, FLAVIN-ADENINE DINUCLEOTIDE, BENZOIC ACID, ... (5 entities in total)
• 機能のキーワード: fad, flavoprotein, oxidoreductase, peroxisome, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 81022.34

構造登録者

Skene, R.J.,Bell, J.A. (登録日: 2022-03-11, 公開日: 2022-06-08, 最終更新日: 2023-10-18)

主引用文献

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

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: 35482677
DOI: 10.1021/acs.jmedchem.2c00118

実験手法

X-RAY DIFFRACTION (1.66 Å)