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La estructura cristalina de rayos X de la fosfodiesterasa 2 en complejo con un inhibidor nanomolar altamente
Jian Zhu1, Qiqi Yang, Dandan Dai
1State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China.
Journal of the American Chemical Society
|August 1, 2013
Resumen
Los investigadores aclararon la estructura de la fosfodiesterasa 2 (PDE2) compleja con un inhibidor selectivo. Esto reveló un nuevo bolsillo inducido por la unión, que mejora la selectividad del inhibidor para el desarrollo de fármacos PDE2.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Estructural Biología estructural.
- Química Medicinal Química medicinal es el campo de la química medicinal.
Sus antecedentes:
- Las enzimas de la fosfodiesterasa humana (PDE) juegan un papel crítico en la señalización celular.
- Comprender la selectividad de los inhibidores a través de las familias de PDE (PDEs 1-11) es crucial para el desarrollo de fármacos dirigidos.
- Los inhibidores selectivos de la PDE2 son de interés terapéutico.
Objetivo del estudio:
- Para determinar la estructura cristalina de rayos X de PDE2 en complejo con un inhibidor selectivo.
- Aclarar la base estructural de la selectividad de los inhibidores hacia la PDE2.
- Informar las estrategias de diseño de fármacos basadas en la estructura para los inhibidores de la PDE.
Principales métodos:
- Cristalografía de rayos X del complejo inhibidor de la PDE2 y apo PDE2.
- Análisis de las interacciones proteína-ligando dentro del sitio activo.
- En silico acoplamiento molecular y perfiles de afinidad.
Principales resultados:
- Se informó de las estructuras cristalinas de rayos X del complejo PDE2-BAY60-7550 (1.9 Å) y apo PDE2 (2.0 Å).
- Identificación de la unión al inhibidor a través del interruptor de glutamina conservado y un nuevo bolsillo hidrofóbico inducido por la unión.
- El acoplamiento molecular confirmó que la bolsa hidrofóbica contribuye significativamente a la afinidad de unión y la selectividad de la PDE2.
Conclusiones:
- El estudio revela un bolsillo inducido por la unión no reportado previamente en el sitio activo de PDE2.
- La explotación de tales bolsillos es una estrategia viable para mejorar la selectividad de los inhibidores en el descubrimiento de fármacos para la EDP.
- Proporciona una base estructural para el diseño de inhibidores de la PDE2 de próxima generación, altamente selectivos.
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