title: Catechol-O-methyltransferase in complex with substituted 3'-deoxyribose bisubstrate inhibitors.
abstract: The biological activity of catechol neurotransmitters such as dopamine in the synapse is modulated by transporters and enzymes. Catechol-O-methyltransferase (COMT; EC 2.1.1.6) inactivates neurotransmitters by catalyzing the transfer of a methyl group from S-adenosylmethionine to catechols in the presence of Mg²⁺. This pathway also inactivates L-DOPA, the standard therapeutic for Parkinson's disease. Depletion of catechol neurotransmitters in the prefrontal cortex has been linked to schizophrenia. The inhibition of COMT therefore promises improvements in the treatment of these diseases. The concept of bisubstrate inhibitors for COMT has been described previously. Here, ribose-modified bisubstrate inhibitors were studied. Three high-resolution crystal structures of COMT in complex with novel ribose-modified bisubstrate inhibitors confirmed the predicted binding mode but displayed subtle alterations at the ribose-binding site. The high affinity of the inhibitors can be convincingly rationalized from the structures, which document the possibility of removing and/or replacing the ribose 3'-hydroxyl group and provide a framework for further inhibitor design.
authors.affiliation: Laboratorium für Organische Chemie, ETH Zürich, Hönggerberg, HCI, CH-8093 Zürich, Switzerland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Ellermann
authors.forename: Christian
authors.initials: C
authors.lastname: Lerner
authors.forename: Guillaume
authors.initials: G
authors.lastname: Burgy
authors.forename: Andreas
authors.initials: A
authors.lastname: Ehler
authors.forename: Caterina
authors.initials: C
authors.lastname: Bissantz
authors.forename: Roland
authors.initials: R
authors.lastname: Jakob-Roetne
authors.forename: Ralph
authors.initials: R
authors.lastname: Paulini
authors.forename: Oliver
authors.initials: O
authors.lastname: Allemann
authors.forename: Heloïse
authors.initials: H
authors.lastname: Tissot
authors.forename: Dan
authors.initials: D
authors.lastname: Grünstein
authors.forename: Martine
authors.initials: M
authors.lastname: Stihle
authors.forename: Francois
authors.initials: F
authors.lastname: Diederich
authors.forename: Markus G
authors.initials: MG
authors.lastname: Rudolph
mesh_terms: D001665:Binding Sites; D002394:Catechol O-Methyltransferase / Q000737:chemistry / Q000378:metabolism; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D003855:Deoxyribose / Q000037:antagonists & inhibitors*; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology; D015195:Drug Design; D007980:Levodopa / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D010300:Parkinson Disease / Q000188:drug therapy; D012266:Ribose / Q000037:antagonists & inhibitors*; D012436:S-Adenosylmethionine / Q000037:antagonists & inhibitors*
chemical_list: D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D007980:Levodopa; D003855:Deoxyribose; D012266:Ribose; D012436:S-Adenosylmethionine; D002394:Catechol O-Methyltransferase; D004298:Dopamine