Bisubstrate inhibitors for the enzyme catechol-O-methyltransferase (COMT): influence of inhibitor preorganisation and linker length between the two substrate moieties on binding affinity.
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.
Lerner
Christian
C
Laboratorium für Organische Chemie, ETH-Hönggerberg, HCI, CH-8093 Zürich, Switzerland.
Masjost
Birgit
B
Ruf
Armin
A
Gramlich
Volker
V
Jakob-Roetne
Roland
R
Zürcher
Gerhard
G
Borroni
Edilio
E
Diederich
François
F
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
D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D004791:Enzyme Inhibitors; D007477:Ions; D002394:Catechol O-Methyltransferase; D008274:Magnesium