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Ligandos alostéricos para los receptores farmacológicamente oscuros GPR68 y GPR65

Xi-Ping Huang^1,2, Joel Karpiak³, Wesley K Kroeze¹

¹Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599-7365, USA.

|November 10, 2015

Resumen

Los investigadores identificaron el lorazepam como un modulador de GPR68, lo que permitió el descubrimiento de nuevos compuestos para los receptores huérfanos acoplados a la proteína G (GPCR). Este enfoque ayuda a comprender las funciones de GPCR y a desarrollar terapias.

Área de la Ciencia:

Farmacología
La bioquímica
La genómica

Sus antecedentes:

Muchos receptores acoplados a proteínas G (GPCR) son receptores "huérfanos" con ligandos desconocidos, lo que limita la investigación funcional y clínica.
GPR68, un receptor de protones, carece de moduladores específicos de moléculas pequeñas, lo que dificulta la investigación biológica.

Objetivo del estudio:

Identificar los moduladores del GPR68 huérfano y desarrollar un enfoque de detección generalizable para los GPCR insuficientemente estudiados.

Principales métodos:

El cribado basado en levaduras identificó al lorazepam como un modulador alostérico positivo de GPR68.
El modelado de homología y el acoplamiento molecular se utilizaron para predecir nuevos moduladores GPR68.
Los ensayos funcionales confirmaron los moduladores previstos, incluida la ogerina, y se aplicaron a GPR65.

Principales resultados:

El lorazepam fue identificado como un modulador alostérico positivo no selectivo para GPR68.
El cribado computacional predijo y validó nuevos moduladores de GPR68, incluido el potente compuesto ogerina.
Ogerin suprimió el recuerdo del miedo en ratones, con efectos dependientes de la presencia de GPR68.
Se descubrieron agonistas alostéricos y moduladores alostéricos negativos para GPR65.

Conclusiones:

Una estrategia combinada de detección física y basada en la estructura descubrió efectivamente ligandos para GPCR huérfanos como GPR68 y GPR65.
Este enfoque facilita el estudio de los GPCR insuficientemente explorados y el desarrollo de nuevas terapias.

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