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In-vivo Detection of Protein-protein Interactions on Micro-patterned Surfaces
Published on: March 19, 2010
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Orientación a las superficies desocupadas en las interfaces proteína-proteína
David Rooklin1, Ashley E Modell1, Haotian Li1
1Department of Chemistry, New York University , New York, New York 10003, United States.
Journal of the American Chemical Society
|August 1, 2017
Resumen
Desarrollamos una estrategia de diseño computacional usando AlphaSpace para crear inhibidores peptidomiméticos que se dirigen a las interacciones proteína-proteína optimizando la ocupación del bolsillo. Este método diseñó con éxito un inhibidor para el objetivo KIX / MLL, lo que demuestra su potencial para el descubrimiento de fármacos.
Área de la Ciencia:
- Diseño computacional de fármacos
- Inhibidores de la interacción proteína-proteína
- Química de las peptidomimetas
Sus antecedentes:
- La orientación de las interfaces proteína-proteína (IPP) con los peptidomiméticos es una estrategia clave para el diseño de inhibidores.
- Este enfoque se basa en imitar los motivos de proteínas nativas, específicamente los residuos de puntos calientes, lo que presenta desafíos de diseño.
- La identificación de bolsas adecuadas para la unión al inhibidor es crucial para optimizar la eficacia.
Objetivo del estudio:
- Para presentar una nueva estrategia de diseño computacional centrada en el bolsillo guiada por AlphaSpace.
- Identificar las bolsas objetivo y desocupadas cerca de los motivos peptidomiméticos para el diseño del inhibidor.
- Para optimizar la unión del inhibidor y la ocupación del bolsillo a través de las interfaces de proteínas.
Principales métodos:
- Utilizó AlphaSpace para representar el espacio de bolsillo como cúmulos alfa.
- Se empleó una estrategia centrada en el bolsillo para guiar la selección de mutaciones de aminoácidos (naturales y no naturales).
- Probó la estrategia en el objetivo KIX / MLL PPI, optimizando un motivo helicoidal dentro de MLL.
- Eficacia del inhibidor validada mediante simulaciones de dinámica molecular y ensayos de polarización por fluorescencia.
Principales resultados:
- Se han identificado con éxito bolsas de alta calidad adecuadas para el diseño de inhibidores.
- Diseñado y optimizado un inhibidor peptidomimético dirigido a la interacción KIX/MLL.
- Se ha demostrado la eficacia del inhibidor diseñado mediante validación computacional y experimental.
Conclusiones:
- La estrategia de diseño computacional guiada por AlphaSpace y centrada en el bolsillo es efectiva para desarrollar inhibidores de PPI.
- Este enfoque permite la optimización de la ocupación del bolsillo para mejorar el rendimiento del inhibidor.
- La estrategia es prometedora para el diseño de terapias novedosas contra objetivos de IPP difíciles.
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