E. Alcalde et al., MOLECULAR MODELING OF (E)-1-ALKYL-4(3)-[2-(1H-AZOLYL)VINYL]-PYRIDINIUM SALTS AND EVALUATION OF THEIR BEHAVIOR TOWARDS CHOLINE-ACETYLTRANSFERASE, Bioorganic & medicinal chemistry, 5(5), 1997, pp. 949-954
A new type of extended pi-system aza-analogue of (E)-4-[2-(1-naphthylv
inyl)]-1-substituted pyridinium salts (NVP+) has been designed and its
inhibitory activity towards choline acetyltransferase (ChAT) has been
evaluated in vitro. Among the several examples of the title quaternar
y salts synthesized 2 and 3, the indolylvinylpyridinium salt 2e is the
only one to show a very low ChAT inhibition. The molecular modeling s
tudy is highly illustrative of their behavior towards ChAT and interac
tion with the recognition site. Thus, several selected cations togethe
r with the reference NVP+ compound la were studied at the PM3 and AM1
levels respectively. At the global minima, all the compounds are plana
r, which, from the electron charge distribution, shows a degree of pol
arization similar to the NVP+ model compound la. However, the fitting
of all optimized structures indicated that only the indole derivative
2e showed the same aromatic fragment orientation as la, which allows u
s to define a volume that is not accessible to ligands in the enzyme a
nd consequently to a refined model of the choline acetyltransferase re
cognition site. (C) 1997 Elsevier Science Ltd.