4XUE

Synthesis and evaluation of heterocyclic catechol mimics as inhibitors of catechol-O-methyltransferase (COMT): Structure with Cmpd27b

Summary for 4XUE

• Entry DOI: 10.2210/pdb4xue/pdb
• Related: 4XUC 4XUD
• Descriptor: Catechol O-methyltransferase, 2-(biphenyl-3-yl)-5-hydroxy-3-methylpyrimidin-4(3H)-one, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: comt, catechol-o-methyltransferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Isoform Soluble: Cytoplasm. Isoform Membrane-bound: Cell membrane; Single-pass type II membrane protein; Extracellular side : P21964
• Total number of polymer chains: 2
• Total formula weight: 49241.04

Authors

Allison, T.,Wolkenberg, S.,Sanders, J.M.,Soisson, S.M. (deposition date: 2015-01-25, release date: 2015-04-15, Last modification date: 2024-02-28)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.3 Å)