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Una pantalla virtual para diversos ligandos: descubrimiento de antagonistas selectivos de los receptores acoplados a
Stanislav Engel1, Amanda P Skoumbourdis, John Childress
1The Clinical Endocrinology Branch and Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Journal of the American Chemical Society
|March 25, 2008
Resumen
Un nuevo método de cribado virtual supera los desafíos en el descubrimiento de fármacos de receptores acoplados a proteínas G (GPCR). Este enfoque identificó nuevos antagonistas para los receptores de la hormona liberadora de tirotropina (TRH-R1 y TRH-R2).
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Farmacología Farmacología.
- Química computacional es la química computacional.
Sus antecedentes:
- El cribado virtual es clave para identificar moléculas pequeñas bioactivas, pero su éxito con los receptores acoplados a proteínas G (GPCR) es limitado.
- Los GPCR presentan desafíos debido a la escasez de datos estructurales y la flexibilidad inherente, lo que complica la detección virtual basada en receptores.
- Los métodos existentes luchan por tener en cuenta la incertidumbre estructural y la flexibilidad en los GPCR.
Objetivo del estudio:
- Desarrollar y validar una metodología in silico para el cribado virtual dirigido al GPCR que aborde la incertidumbre estructural.
- Identificar nuevos antagonistas de moléculas pequeñas para los receptores de la hormona liberadora de tirotropina (TRH-R1 y TRH-R2).
Principales métodos:
- Desarrolló una nueva metodología in silico para mitigar la incertidumbre estructural en el cribado virtual de GPCRs.
- Examinó un millón de compuestos de una base de datos virtual utilizando la metodología desarrollada.
- Se seleccionaron 100 compuestos diversos para la validación experimental, incluido el análisis mutacional de los receptores de TRH.
Principales resultados:
- Se identificaron cinco antagonistas estructuralmente diversos para los receptores de la hormona liberadora de tirotropina (TRH-R1 y TRH-R2).
- La quiralidad fue crucial para la afinidad de unión, con un estereoisómero que muestra 13 veces más selectividad para TRH-R1 que para TRH-R2.
- El análisis mutacional confirmó el modo de unión de los antagonistas de moléculas pequeñas identificados.
Conclusiones:
- El nuevo enfoque de cribado virtual identifica eficazmente los antagonistas de GPCR a pesar de los desafíos estructurales.
- Esta metodología es prometedora para descubrir nuevos agonistas y antagonistas para otros objetivos de GPCR.
- Los hallazgos destacan la importancia de la quiralidad en el diseño del antagonista del receptor TRH.
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