title: Bisubstrate inhibitors for the enzyme catechol-O-methyltransferase (COMT): influence of inhibitor preorganisation and linker length between the two substrate moieties on binding affinity.
abstract: Inhibition of the enzyme catechol-O-methyltransferase (COMT) is an important approach in the treatment of Parkinson's disease. A series of new potent bisubstrate inhibitors for COMT, resulting from X-ray structure-based design and featuring adenosine and catechol moieties have been synthesised. Biological results show a large dependence of binding affinity on inhibitor preorganisation and the length of the linker between nucleoside and catechol moieties. The most potent bisubstrate inhibitor for COMT has an IC50 value of 9 nM. It exhibits competitive kinetics for the SAM and mixed inhibition kinetics for the catechol binding site. Its bisubstrate binding mode was confirmed by X-ray structure analysis of the ternary complex formed by the inhibitor, COMT and a Mg2+ ion.
authors.affiliation: Laboratorium für Organische Chemie, ETH-Hönggerberg, HCI, CH-8093 Zürich, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Lerner
authors.forename: Birgit
authors.initials: B
authors.lastname: Masjost
authors.forename: Armin
authors.initials: A
authors.lastname: Ruf
authors.forename: Volker
authors.initials: V
authors.lastname: Gramlich
authors.forename: Roland
authors.initials: R
authors.lastname: Jakob-Roetne
authors.forename: Gerhard
authors.initials: G
authors.lastname: Zürcher
authors.forename: Edilio
authors.initials: E
authors.lastname: Borroni
authors.forename: François
authors.initials: F
authors.lastname: Diederich
mesh_terms: D001665:Binding Sites; D001667:Binding, Competitive; D002394:Catechol O-Methyltransferase / Q000737:chemistry*; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000737:chemistry; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D007477:Ions; D007700:Kinetics; D008274:Magnesium / Q000737:chemistry; D008956:Models, Chemical; D008958:Models, Molecular; D011485:Protein Binding; D013696:Temperature
chemical_list: D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D004791:Enzyme Inhibitors; D007477:Ions; D002394:Catechol O-Methyltransferase; D008274:Magnesium