A SEMIEMPIRICAL STUDY ON INHIBITION OF CATECHOL O-METHYLTRANSFERASE BY SUBSTITUTED CATECHOLS

Citation
M. Ovaska et A. Yliniemela, A SEMIEMPIRICAL STUDY ON INHIBITION OF CATECHOL O-METHYLTRANSFERASE BY SUBSTITUTED CATECHOLS, Journal of computer-aided molecular design, 12(3), 1998, pp. 301-307
Citations number
30
Categorie Soggetti
Biology,Biophysics,"Computer Science Interdisciplinary Applications
ISSN journal
0920654X
Volume
12
Issue
3
Year of publication
1998
Pages
301 - 307
Database
ISI
SICI code
0920-654X(1998)12:3<301:ASSOIO>2.0.ZU;2-I
Abstract
Catechol and endogenous catechol derivatives are readily methylated by catechol O-methyltransferase (COMT). In contrast, many catechol deriv atives possessing electronegative substituents are potent COMT inhibit ors. The X-ray structure of the active site of COMT suggests that the methylation involves a lysine as a general base. The lysine can activa te one of the catecholic hydroxyl groups for a nucleophilic attack on the active methyl group of the coenzyme S-adenosyl-L-methionine (AdoMe t). We studied the effect of dinitrosubstitution of the catecholic rin g at the semiempirical PM3 level on the methylation reaction catalysed by COMT. The electronegative nitro groups make the ionized catechol h ydroxyls less nucleophilic than the corresponding hydroxyl groups of t he nonsubstituted catechol. As a consequence, dinitrocatechol is not m ethylated but is instead a potent COMT inhibitor. The implications of this mechanism to the design of COMT inhibitors are discussed.