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

• Published in: Journal of computer-aided molecular design Vol. 12; no. 3; pp. 301 - 307
• Main Authors: Ovaska, M, Yliniemelä, A
• Format: Journal Article
• Language: English
• Published: Netherlands Springer Nature B.V 01.05.1998
• Subjects: Binding Sites; Catechol; Catechol O-Methyltransferase - chemistry; Catechol O-Methyltransferase - metabolism; Catechol O-Methyltransferase Inhibitors; Catechols - pharmacology; Derivatives; Electronegativity; Enzyme Inhibitors - pharmacology; Enzymes; Hydroxyl groups; Inhibitors; Lysine; Methylation; Models, Molecular; Thermodynamics; X-rays
• ISSN: 0920-654X; 1573-4951
• DOI: 10.1023/A:1007965026738

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.