Bisubstrate inhibitors for the enzyme catechol-O-methyltransferase (COMT): influence of inhibitor preorganisation and linker length between the two substrate moieties on binding affinity.
Org Biomol Chem
; 1(1): 42-9, 2003 Jan 07.
Article
en En
| MEDLINE
| ID: mdl-12929389
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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Catecol O-Metiltransferasa
/
Inhibidores Enzimáticos
/
Inhibidores de Catecol O-Metiltransferasa
Idioma:
En
Revista:
Org Biomol Chem
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2003
Tipo del documento:
Article
País de afiliación:
Suiza