Bisubstrate inhibitors for the enzyme catechol-O-methyltransferase (COMT): influence of inhibitor preorganisation and linker length between the two substrate moieties on binding affinity

Literature Information

Publication Date 2002-11-26
DOI 10.1039/B208690P
Impact Factor 3.876
Authors

Christian Lerner, Birgit Masjost, Armin Ruf, Volker Gramlich, Roland Jakob-Roetne, Gerhard Zürcher, Edilio Borroni, François Diederich


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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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Organic & Biomolecular Chemistry

Organic & Biomolecular Chemistry
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Organic & Biomolecular Chemistry (OBC) publishes original and high impact research and reviews in organic chemistry. We welcome research that shows new or significantly improved protocols or methodologies in total synthesis, synthetic methodology or physical and theoretical organic chemistry as well as research that shows a significant advance in the organic chemistry or molecular design aspects of chemical biology, catalysis, supramolecular and macromolecular chemistry, theoretical chemistry, mechanism-oriented physical organic chemistry, medicinal chemistry or natural products. Articles published in the journal should report new work which makes a highly-significant impact in the field. Routine and incremental work is generally not suitable for publication in the journal. More details about key areas of our scope are below. In all cases authors should include in their article clear rationale for why their research has been carried out.

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