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X-ray Crystal Structure of a Bisubstrate Inhibitor Bound to the Enzyme Catechol-O-methyltransferase: A Dramatic Effect of Inhibitor Preorganization on Binding Affinity We thank F. Hoffmann–La Roche for generous support of this work. We are grateful to P. Malherbe for the cloning of COMT, P. Caspers for the expression of COMT, A. Cesura for enzyme purification, B. Wipf for fermentation, and H. W. Lahm for sequencing.
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2001
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Binding AffinityMolecular BiologyEnzyme PurificationS DiseaseMolecular PharmacologyProtein X-ray CrystallographyP. CaspersDopamine—its TargetStructure-function Enzyme KineticsNeurochemistryInhibitory ActivityBiochemistryBiocatalysisMechanism Of ActionNeuropharmacologyDopaminePharmacologyStructural BiologyDopamine ResearchIc50 ValueNatural SciencesEnzyme CatalysisEnzyme SpecificityMedicineSmall MoleculesDrug Discovery
With an IC50 value of 9 nM, 1 is the most potent known disubstrate inhibitor for catechol-O-methyltransferase (COMT). Inhibition of COMT is of significant interest in the therapy of Parkinsonapos;s disease since it ensures that a larger percentage of orally administered L-dopa reaches—in the form of dopamine—its target in the brain. The X-ray crystal structure of a complex formed by COMT and 1 has been solved at 2.6-Å resolution.