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Atamiento de ligandos dirigido por uracilo: una estrategia eficiente para el desarrollo de inhibidores de la
Yu Lin Jiang1, Daniel J Krosky, Lauren Seiple
1Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA.
Journal of the American Chemical Society
|December 8, 2005
Resumen
Los investigadores desarrollaron una nueva estrategia de atadura de ligandos dirigida al uracilo para encontrar inhibidores de la glicosilasa de ADN de uracilo (UNG). Este método identificó rápidamente nuevos inhibidores de moléculas pequeñas dirigidos a la enzima.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Molecular Biología Molecular
- Enzimología Enzimología.
Sus antecedentes:
- La glicosilasa de ADN de Uracil (UNG) es crucial para la reparación del ADN, la diversidad de anticuerpos, la replicación viral y la eficacia de los medicamentos contra el cáncer.
- UNG utiliza un mecanismo de reconocimiento extrahelical para extirpar las bases de uracilo del ADN.
- Dirigirse a UNG con moléculas pequeñas es una estrategia prometedora para la intervención terapéutica.
Objetivo del estudio:
- Desarrollar una estrategia eficiente para el descubrimiento de inhibidores de moléculas pequeñas de la glicosilasa de ADN de uracilo humano (UNG).
- Para aprovechar el mecanismo de reconocimiento extrahelical de la enzima para el diseño del inhibidor.
- Identificar rápidamente nuevos inhibidores con potenciales aplicaciones terapéuticas.
Principales métodos:
- Desarrolló una estrategia de atadura de ligandos dirigida al uracilo utilizando ligandos de aldehído de uracilo y enlaces de alquiloxiamina.
- Aprovechó el mecanismo de reconocimiento extrahelical para atacar el sitio activo de la UNG.
- Se exploraron aleatoriamente bolsas de unión periféricas mediante la unión a diversos elementos de unión a aldehídos sin purificación de compuestos.
Principales resultados:
- Se identificaron con éxito los primeros inhibidores de moléculas pequeñas de la UNG humana con afinidades de unión micromolar a submicromolar.
- Descubrió que los ligandos a base de uracilo se unen tanto al sitio activo como a un segundo sitio no competitivo.
- El sitio no competitivo sugiere un sitio de unión transitorio para el uracilo durante el mecanismo de UNG.
Conclusiones:
- La estrategia de enlace de ligando dirigido a uracilo es un método eficiente para descubrir inhibidores de UNG.
- La identificación de un segundo sitio de unión proporciona nuevos conocimientos sobre el mecanismo de reconocimiento de sustrato de UNG.
- Esta estrategia general puede adaptarse para desarrollar inhibidores para otras enzimas de reconocimiento de nucleobases, incluidas las enzimas de reparación de ADN.
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