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El modelado de complejos de proteínas y ligandos de alta confianza por acoplamiento guiado por RMN permite la

Andrew Proudfoot¹, Dirksen E Bussiere¹, Andreas Lingel^1,2

¹Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.

Journal of the American Chemical Society

|December 1, 2017

Resumen

Este estudio introduce un nuevo protocolo de acoplamiento guiado por RMN para el diseño de fármacos basado en la estructura. El método genera con éxito modelos complejos de proteína-ligando de alta calidad, lo que permite la optimización prospectiva de fragmentos de fármacos.

Área de la Ciencia:

La bioquímica
Biología estructural
Descubrimiento de drogas

Sus antecedentes:

El diseño de fármacos basado en la estructura se basa en la caracterización del complejo proteico-ligando, generalmente a través de la cristalografía de rayos X.
El éxito de la cristalografía es limitado para las proteínas dinámicas y los aglutinantes débiles, lo que dificulta la optimización del fármaco.
Esta limitación restringe la diversidad del andamio químico y la exploración en el descubrimiento de fármacos.

Objetivo del estudio:

Desarrollar un robusto protocolo de acoplamiento guiado por restricción de RMN para generar modelos complejos de proteína y ligando de alta calidad.
Para superar las limitaciones de la cristalografía de rayos X en el descubrimiento de fármacos para objetivos desafiantes.
Para permitir la optimización prospectiva de los fragmentos en conectores más potentes.

Principales métodos:

Utilizó un nuevo protocolo de acoplamiento guiado por RMN.
Proteínas combinadas altamente etiquetadas con metilo con distancias intermoleculares determinadas experimentalmente.
Generó restricciones de distancia proteína-ligando completas para impulsar el acoplamiento y determinar la conformación del ligando.

Principales resultados:

Se generaron con éxito modelos de alta calidad de complejos proteico-ligandos.
Demostró la utilidad y el rendimiento del protocolo de acoplamiento guiado por RMN.
Se logró una optimización prospectiva de los fragmentos cristalográficamente intratables que chocan con aglutinantes más potentes.

Conclusiones:

El protocolo de acoplamiento guiado por restricción de RMN es una herramienta poderosa para el diseño de fármacos basado en la estructura.
Este método supera las limitaciones asociadas con la cristalografía de rayos X para objetivos difíciles.
Permite una exploración mejorada del espacio químico y la optimización de nuevos fármacos candidatos.

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