The Electronic Influence on the Active Site-Directed Inhibition of Acetylcholinesterase by N-aryl-Substituted Succinimides

Abstract

A computational docking approach, in combination with the Hammett relationship, has been employed to evaluate the elec- tronic influence of substituents on ligand binding and the active site-directed inhibitory potency on acetylcholinesterase using nine N-aryl-substituted succinimides. Our results indicate that electron- withdrawing groups attached to benzene moiety of the compounds favor the inhibitory potency while electron-donating groups do not. This fact was confirmed by performing kinetic experiments on ace- tylcholinesterase from Electrophorus electricus; the experiments showed that para-substituted-NO 2 compound inhibits better than para-substituted-OMe and -H derivatives. This approach may be use- ful for the rationalization of drugs design, as well as the mechanism of the active site.