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The Synthesis, Characterization and Reactivity of a Series of Ruthenium N-triphosPh Complexes
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Dirigiéndose a grandes sitios activos de la quinasa con complejos de rutenio octaédricos rígidos y voluminosos
Jasna Maksimoska1, Li Feng, Klaus Harms
1The Wistar Institute and University of Pennsylvania, Department of Chemistry, Philadelphia, Pennsylvania 19104, USA.
Journal of the American Chemical Society
|November 1, 2008
Resumen
Los investigadores desarrollaron nuevos complejos de rutenio para atacar grandes sitios de unión de ATP de la proteína quinasa. Estos compuestos octaédricos voluminosos, como Lambda-FL172, inhiben eficazmente el PAK1, lo que demuestra una nueva estrategia para el diseño de inhibidores de la quinasa.
Área de la Ciencia:
- Química Medicinal La Química Medicinal es el campo de la Química Medicinal.
- Biología Estructural Biología estructural.
- Química Inorgánica La química inorgánica es la química inorgánica.
Sus antecedentes:
- La orientación de las proteínas quinasas es crucial para el tratamiento de diversas enfermedades.
- Los grandes sitios de unión de ATP en las quinasas plantean desafíos para el diseño de inhibidores selectivos.
- Los complejos de rutenio ofrecen propiedades estructurales y electrónicas únicas para el desarrollo de fármacos.
Objetivo del estudio:
- Presentar una nueva estrategia para el desarrollo de inhibidores de la proteína quinasa utilizando complejos de rutenio octaédricos voluminosos.
- Diseñar y sintetizar inhibidores basados en rutenio dirigidos a las quinasas con grandes sitios de unión al ATP.
- Para dilucidar el mecanismo de unión de estos complejos dentro del sitio activo de la quinasa.
Principales métodos:
- Síntesis de complejos octaédricos de rutenio (Lambda-FL172, Lambda-FL411) mediante la modificación de un conocido andamio inhibidor (NP309).
- Co-cristalización de la quinasa PAK1 con el complejo de rutenio Lambda-FL172.
- Cristalografía de rayos X para determinar la estructura cocristalina de alta resolución (1,65 Å).
Principales resultados:
- Conversión exitosa de un inhibidor GSK3/Pim1 en un inhibidor PAK1 utilizando complejos octaédricos de rutenio.
- La gran esfera de coordinación de Lambda-FL172 se ajusta efectivamente al sitio activo de PAK1.
- La estructura cocristalina revela cómo el complejo actúa como un "palo de jardín" para distinguir entre sitios de unión similares.
Conclusiones:
- Los complejos de rutenio octaédricos voluminosos y rígidos son andamios efectivos para atacar grandes sitios de unión al ATP en las proteínas cinasas.
- Este enfoque permite el diseño de inhibidores selectivos mediante la explotación de las diferencias estéricas en los sitios activos de la quinasa.
- Los complejos de rutenio representan una plataforma prometedora para el desarrollo de nuevas terapias dirigidas a la quinasa.
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