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Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
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Explorando fuentes experimentales de múltiples conformaciones de proteínas en el diseño de fármacos basado en la
Kelly L Damm1, Heather A Carlson
1Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109-1065, USA.
Journal of the American Chemical Society
|June 9, 2007
Resumen
La incorporación de la flexibilidad de las proteínas utilizando múltiples conformaciones mejora el diseño de fármacos. Los conjuntos de RMN ofrecen una representación del sitio activo más general y precisa que las estructuras de cristal para el diseño de fármacos basados en la estructura.
Área de la Ciencia:
- Biología estructural Biología estructural.
- Química computacional es la química computacional.
- Descubrimiento de fármacos.
Sus antecedentes:
- La flexibilidad de las proteínas es crucial para el diseño preciso de fármacos basados en la estructura.
- En trabajos anteriores se utilizaron conformaciones generadas por computadora para el modelado de farmacóforos de la proteasa 1 del virus de la inmunodeficiencia humana (VIH-1p).
Objetivo del estudio:
- Para comparar la utilidad de los conjuntos de RMN frente a las estructuras cristalinas para generar modelos farmacóforos de estructura múltiple de proteínas (MPS).
- Evaluar el impacto de la flexibilidad de las proteínas en el diseño de fármacos basados en la estructura para el VIH-1p.
Principales métodos:
- Modelos generados de farmacóforos MPS utilizando un conjunto de RMN y una colección de estructuras cristalinas del VIH-1p.
- Comparó el rendimiento de estos modelos con los modelos derivados de las conformaciones de una sola proteína.
- Evaluó la capacidad de los modelos para discriminar los inhibidores conocidos de las moléculas señuelo.
Principales resultados:
- Tanto el conjunto de RMN como los modelos MPS basados en la estructura cristalina discriminaron con éxito a los inhibidores del VIH-1p.
- Los modelos MPS superaron a los modelos de una sola conformación.
- Un conjunto de RMN exhibió una mayor variación estructural que un gran conjunto de estructuras cristalinas.
- El modelo MPS derivado de RMN proporcionó la representación más general y precisa del sitio activo.
Conclusiones:
- El modelado de farmacóforos de múltiples estructuras de proteínas mejora el diseño de fármacos basado en la estructura.
- Los conjuntos de RMN son valiosos para capturar la flexibilidad de las proteínas y generar modelos robustos de diseño de fármacos.
- Este estudio aboga por el uso de modelos de RMN en el diseño de fármacos basados en la estructura.
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