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Vol. 59, Issue 2, 393-402, February 2001
Department of Pharmacy, Viikki Drug Discovery Technology Center,
University of Helsinki, Finland (P.L., J.T.) and Orion Pharma,
Molecular Biology and Target Protein Research, Viikki Biocenter,
Helsinki, Finland (I.U.)
Molecular mechanisms determining the turn-over rate and specificity of
catechol O-methylation were studied by combining enzyme kinetic measurements, computational modeling of substrate properties and fitting ligands in a 3D model of the active site of the enzyme. Enzyme kinetic measurements were carried out for 46 compounds, including most clinically used catechol drugs, by using recombinant human soluble catechol O-methyltransferase (COMT). The
most important mechanism decreasing the turnover rate and increasing
affinity was the electron withdrawing effect of substituents. Several
other mechanisms by which substituents affected reactivity and affinity were identified. Highest turnover rates were determined for
unsubstituted catechol and pyrogallol. Pyrogallol derivatives generally
seemed to be more specific substrates than catechols. Catecholestrogens were the most specific endogenous substrates, whereas catecholamines were rather poor substrates. Among the catechol drugs used in the
L-DOPA treatment of Parkinson's disease, the COMT
inhibitors entacapone and tolcapone were not methylated, whereas the
DOPA decarboxylase inhibitor benserazide was 15 times more specific substrate than L-DOPA, the target of COMT inhibition. The
structure-activity relationships found allow the prediction of
reactivity, affinity, and specificity with useful accuracy for
catechols with a wide range of structures and properties. The knowledge
can be used in the evaluation of metabolic interactions of endogenous
catechols, drugs and dietary catechols, and in the designing of drugs
with the catechol pharmacophore.
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