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

A computational docking approach, in combination with the Hammett relationship, has been employed to evaluate the electronic 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 acetylcholinesterase from Electrophorus electricus; the experiments showed that para-substituted-NO2 compound inhibits better than para-substituted-OMe and -H derivatives. This approach may be useful for the rationalization of drugs design, as well as the mechanism of the active site.