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Energéticas del desplazamiento de las moléculas de agua de los sitios de unión a las proteínas: consecuencias para la
Julien Michel1, Julian Tirado-Rives, William L Jorgensen
1Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA.
Journal of the American Chemical Society
|September 26, 2009
Resumen
Las modificaciones en el diseño de fármacos que desplazan el agua unida a proteínas pueden mejorar la afinidad de los ligandos. Sin embargo, el éxito depende del equilibrio energético entre la eliminación del agua y las nuevas interacciones, lo que requiere un análisis termodinámico completo para predicciones precisas.
Área de la Ciencia:
- Química computacional es la química computacional.
- Descubrimiento de fármacos.
- La biofísica es la biofísica.
Sus antecedentes:
- Mejorar la afinidad de la molécula de plomo es una estrategia clave de diseño de fármacos.
- El desplazamiento de las moléculas de agua ordenadas de los sitios de unión a las proteínas es uno de esos enfoques.
- Los resultados energéticos del desplazamiento del agua no siempre son predecibles.
Objetivo del estudio:
- Para aclarar la energética del desplazamiento de las moléculas de agua ordenadas en los sitios de unión a las proteínas.
- Investigar por qué modificaciones estructurales similares producen diferentes cambios de afinidad.
- Para proporcionar una guía computacional precisa para la optimización de plomo.
Principales métodos:
- Cálculos de perturbaciones de energía libre.
- Simulaciones de mecánica estadística de Monte Carlo.
- Análisis de las series de ligandos dirigidos a la escitalona deshidratasa, la p38-alfaMAP quinasa y la EGFR quinasa.
Principales resultados:
- Los cambios en la afinidad de la modificación del ligando se correlacionan con la facilidad de desplazamiento de las moléculas de agua.
- La afinidad de unión puede disminuir si la energía de remoción de agua no es compensada por nuevas interacciones.
- Una predicción precisa requiere identificar ubicaciones de agua y calcular los cambios de energía libre asociados.
Conclusiones:
- El análisis termodinámico completo es esencial para modificaciones precisas en el diseño de fármacos.
- La modificación directa de los ligandos en los cálculos puede dar resultados engañosos.
- Comprender la energética de las moléculas de agua es crucial para una optimización exitosa del plomo.
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