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Acetilcolinesterasa compleja con ligandos bivalentes relacionados con la huperzina a: evidencia experimental para la
Dawn M Wong1, Harry M Greenblatt, Hay Dvir
1Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
Journal of the American Chemical Society
|January 9, 2003
Resumen
Los nuevos inhibidores diméricos de la acetilcolinesterasa (AChE), derivados de las huperidonas, muestran una mayor potencia al unirse a ambos sitios activos de Torpedo californica AChE. Las diferencias estructurales entre el AChE de peces y ratas explican la eficacia variable del inhibidor.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Estructural Biología estructural.
- Farmacología Farmacología.
Sus antecedentes:
- Los inhibidores de la acetilcolinesterasa (AChE) son cruciales para controlar los síntomas de la enfermedad de Alzheimer.
- (-) -Huperzina A ((-) -HupA) es un conocido inhibidor de AChE, pero se buscan alternativas más potentes.
- Los dímeros ligados al alquileno de la 5-amino-5,6,7,8-tetrahidroquinolinona (hupiridona, 1a) muestran una mayor inhibición de la AChE.
Objetivo del estudio:
- Aclarar la base estructural para la potencia inhibidora mejorada de los dímeros de hupiridona contra el AChE.
- Para comparar los modos de unión y los efectos inhibidores de dos dímeros de hupiridona, (S,S) - - - bis - 10 - hupiridona - 2a y (S,S) - bis - 12 - hupiridona - 2b, en Torpedo californica AChE (TcAChE).
Principales métodos:
- Se empleó cristalografía de rayos X para determinar las estructuras de TcAChE complejo con dimeros de hupiridona a una resolución de 2,15 Å.
- Diferencia Las técnicas de Fourier se utilizaron para la solución de la estructura.
- Se realizaron ensayos de inhibición para cuantificar las afinidades de unión de los dímeros y (-) -Hup.A.
Principales resultados:
- Ambos inhibidores diméricos abarcaron la garganta del sitio activo de TcAChE, con una unidad de hupiridona que se une al sitio aniónico periférico y la otra al subsitio aniónico activo.
- (-) - 2a exhibió una afinidad significativamente mayor para TcAChE que (-) - 2b y (-) -HupA.
- Las diferencias estructurales en la garganta del sitio activo, particularmente el ancho de la garganta y la orientación de los residuos, entre TcAChE y AChE de rata explican las diferencias de potencia inhibidora observadas.
Conclusiones:
- La mayor afinidad de los análogos diméricos de hupiridona para AChE se atribuye a su unión bivalente a ambos sitios aniónicos.
- Las variaciones estructurales en la garganta del sitio activo de AChE dictan la potencia y la selectividad de diferentes inhibidores.
- Estos hallazgos proporcionan información valiosa para el diseño de inhibidores AChE mejorados para aplicaciones terapéuticas.
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