RESUMEN
Acetylcholinesterase (AChE), a key enzyme in the central and peripheral nervous systems, is the principal target of organophosphorus nerve agents. Quaternary oximes can regenerate AChE activity by displacing the phosphyl group of the nerve agent from the active site, but they are poorly distributed in the central nervous system. A promising reactivator based on tetrahydroacridine linked to a nonquaternary oxime is also an undesired submicromolar reversible inhibitor of AChE. X-ray structures and molecular docking indicate that structural modification of the tetrahydroacridine might decrease inhibition without affecting reactivation. The chlorinated derivative was synthesized and, in line with the prediction, displayed a 10-fold decrease in inhibition but no significant decrease in reactivation efficiency. X-ray structures with the derivative rationalize this outcome. We thus show that rational design based on structural studies permits the refinement of new-generation pyridine aldoxime reactivators that may be more effective in the treatment of nerve agent intoxication.
Asunto(s)
Reactivadores de la Colinesterasa/química , Reactivadores de la Colinesterasa/farmacología , Agentes Nerviosos/toxicidad , Relación Estructura-Actividad , Acetilcolinesterasa/química , Acetilcolinesterasa/metabolismo , Animales , Dominio Catalítico , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos/métodos , Proteínas de Peces/química , Proteínas de Peces/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Agentes Nerviosos/química , Cloruro de Obidoxima/farmacología , Compuestos Organofosforados/química , Compuestos Organofosforados/toxicidadRESUMEN
Structure-based virtual screening of two libraries containing 567â¯981 molecules was used to discover novel, selective BuChE inhibitors, which are potentially superior symptomatic treatments in late-stage Alzheimer's disease. Compound 16 was identified as a highly selective submicromolar inhibitor of BuChE (huBuChE IC50 = 0.443 µM) with high permeability in the PAMPA-BBB model. The X-ray crystal structure of huBuChE in complex with 16 revealed the atomic-level interactions and offers opportunities for further development of the series.