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¿Cómo encuentra una molécula de fármaco su sitio de unión objetivo?
Yibing Shan1, Eric T Kim, Michael P Eastwood
1D. E. Shaw Research, New York, New York 10036, USA.
Journal of the American Chemical Society
|May 7, 2011
Resumen
Las simulaciones de dinámica molecular capturaron moléculas de fármacos como el dasatinib que se unen a las proteínas diana, revelando el proceso a nivel atómico. Este método ayuda en el descubrimiento de nuevos sitios de unión de fármacos, especialmente para los inhibidores alostéricos.
Área de la Ciencia:
- La biofísica es la biofísica.
- Química computacional es la química computacional.
- Farmacología Farmacología.
Sus antecedentes:
- La comprensión de las interacciones fármaco-objetivo es crucial para el desarrollo de fármacos.
- La caracterización experimental de las vías de unión de fármacos sigue siendo un desafío.
- Los principios termodinámicos de la unión molecular están establecidos, pero carecen de detalles dinámicos.
Objetivo del estudio:
- Para simular y visualizar el proceso completo a nivel atómico de unión fármaco-proteína.
- Para investigar el papel de las conformaciones intermedias y las moléculas de agua en la unión.
- Desarrollar una nueva técnica de simulación para identificar sitios de unión de fármacos, incluidos los alostéricos.
Principales métodos:
- Se realizaron simulaciones no guiadas y largas de dinámica molecular.
- Los ligandos (dasatinib, PP1) fueron colocados aleatoriamente cerca de la proteína diana (Src quinasa).
- Las simulaciones rastrearon todo el proceso de unión desde el contacto inicial hasta la formación compleja.
Principales resultados:
- Las simulaciones reproducen con éxito complejos fármaco-proteína cristalográficamente determinados.
- Las trayectorias continuas a nivel atómico revelaron conformaciones de enlace intermedias.
- Se aclaró el papel de las moléculas de agua en la vía de unión.
Conclusiones:
- El método de simulación no guiada captura efectivamente los eventos de unión fármaco-proteína.
- Esta técnica proporciona una visión sin precedentes de los procesos de unión dinámica.
- El enfoque es valioso para descubrir nuevos sitios de unión alostérica y desarrollar nuevos inhibidores.
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