4XUD

Synthesis and evaluation of heterocyclic catechol mimics as inhibitors of catechol-O-methyltransferase (COMT): Structure with Cmpd32 ([1-(biphenyl-3-yl)-5-hydroxy-4-oxo-1,4-dihydropyridin-3-yl]boronic acid)

4XUD の概要

• エントリーDOI: 10.2210/pdb4xud/pdb
• 関連するPDBエントリー: 4XUC 4XUE
• 分子名称: Catechol O-methyltransferase, [1-(biphenyl-3-yl)-5-hydroxy-4-oxo-1,4-dihydropyridin-3-yl]boronic acid, MAGNESIUM ION, ... (6 entities in total)
• 機能のキーワード: comt, catechol-o-methyltransferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Isoform Soluble: Cytoplasm. Isoform Membrane-bound: Cell membrane; Single-pass type II membrane protein; Extracellular side : P21964
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 25184.98

構造登録者

Allison, T.,Wolkenberg, S.,Sanders, J.M.,Soisson, S.M. (登録日: 2015-01-25, 公開日: 2015-04-15, 最終更新日: 2023-09-27)

主引用文献

Harrison, S.T.,Poslusney, M.S.,Mulhearn, J.J.,Zhao, Z.,Kett, N.R.,Schubert, J.W.,Melamed, J.Y.,Allison, T.J.,Patel, S.B.,Sanders, J.M.,Sharma, S.,Smith, R.F.,Hall, D.L.,Robinson, R.G.,Sachs, N.A.,Hutson, P.H.,Wolkenberg, S.E.,Barrow, J.C.
Synthesis and Evaluation of Heterocyclic Catechol Mimics as Inhibitors of Catechol-O-methyltransferase (COMT).
Acs Med.Chem.Lett., 6:318-323, 2015

PubMed Abstract: 3-Hydroxy-4-pyridinones and 5-hydroxy-4-pyrimidinones were identified as inhibitors of catechol-O-methyltransferase (COMT) in a high-throughput screen. These heterocyclic catechol mimics exhibit potent inhibition of the enzyme and an improved toxicity profile versus the marketed nitrocatechol inhibitors tolcapone and entacapone. Optimization of the series was aided by X-ray cocrystal structures of the novel inhibitors in complex with COMT and cofactors SAM and Mg(2+). The crystal structures suggest a mechanism of inhibition for these heterocyclic inhibitors distinct from previously disclosed COMT inhibitors.

PubMed: 25815153
DOI: 10.1021/ml500502d

実験手法

X-RAY DIFFRACTION (2.4 Å)