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A semiempirical study on inhibition of catechol O-methyltransferase by substituted catechols.

Authors
  • Ovaska, M
  • Yliniemelä, A
Type
Published Article
Journal
Journal of computer-aided molecular design
Publication Date
May 01, 1998
Volume
12
Issue
3
Pages
301–307
Identifiers
PMID: 9749372
Source
Medline
License
Unknown

Abstract

Catechol and endogenous catechol derivatives are readily methylated by catechol O-methyltransferase (COMT). In contrast, many catechol derivatives possessing electronegative substituents are potent COMT inhibitors. The X-ray structure of the active site of COMT suggests that the methylation involves a lysine as a general base. The lysine can activate one of the catecholic hydroxyl groups for a nucleophilic attack on the active methyl group of the coenzyme S-adenosyl-L-methionine (AdoMet). We studied the effect of dinitrosubstitution of the catecholic ring at the semiempirical PM3 level on the methylation reaction catalysed by COMT. The electronegative nitro groups make the ionized catechol hydroxyls less nucleophilic than the corresponding hydroxyl groups of the non-substituted catechol. As a consequence, dinitrocatechol is not methylated but is instead a potent COMT inhibitor. The implications of this mechanism to the design of COMT inhibitors are discussed.

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