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
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.