The Electronic Influence on the Active Site-Directed Inhibition of Acetylcholinesterase by N-aryl-Substituted Succinimides
DOI:
https://doi.org/10.29356/jmcs.v51i4.1286Keywords:
Acetylcholinesterase, Hammett Relationship, docking, N-aryl-substituted-succinimidesAbstract
Abstract. 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 electronwithdrawing 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 tan 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.
Resumen. La aproximación por docking, en combinación con la relación de Hammett han sido empleadas conjuntamente para evaluar la influencia electrónica de sustituyentes sobre la unión del ligante y la potencia inhibitoria de la enzima acetilcolinesterasa de 9 N-aril-succinimidas sustituidas. Nuestros resultados indican que grupos electro-atractores favorecen su potencia inhibitoria, mientras que los electro-donadores no lo hacen. Este hecho fue confirmado experimentalmente sobre AChE de Electrophorus electricus; donde el grupo p–NO2 la inhibe de manera más potente que aquellos derivados con grupos p-OMe y –H. Esta aproximación podría ser utilizada para racionalizar tanto el diseño de fármacos, así como el mejor entendimiento del mecanismo de unión sobre el sitio activo.
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