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Las estructuras de los receptores 5-HT2C revelan la base estructural de la polifarmacología GPCR
Yao Peng1, John D McCorvy2, Kasper Harpsøe3
1iHuman Institute, ShanghaiTech University, Shanghai 201210, China; Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming 650500, China; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Cell
|February 6, 2018
Resumen
La comprensión de las interacciones farmacológicas con múltiples objetivos, conocida como polifarmacología, es clave para el tratamiento de enfermedades como la obesidad y la esquizofrenia. Este estudio revela ideas estructurales sobre cómo los medicamentos se unen a los receptores de serotonina, ayudando al diseño de medicamentos futuros para enfermedades complejas.
Área de la Ciencia:
- La neurociencia
- Farmacología
- Biología estructural
Sus antecedentes:
- La polifarmacología, donde los medicamentos interactúan con múltiples objetivos, es crucial para la eficacia terapéutica en el tratamiento de enfermedades complejas.
- Los receptores de serotonina, particularmente el 5-HT2C, son objetivos clave para enfermedades como la obesidad, el abuso de drogas y la esquizofrenia.
- El desarrollo de ligandos o fármacos selectivos con perfiles polifarmacológicos definidos para los receptores acoplados a proteínas G (GPCR) presenta desafíos significativos.
Objetivo del estudio:
- Para aclarar la base estructural de la polifarmacología en GPCRs.
- Proporcionar información mecanicista sobre las interacciones ligando-receptor y las acciones farmacológicas.
- Facilitar el diseño racional de fármacos para los GPCR mediante la comprensión de los patrones de unión ligando-receptor.
Principales métodos:
- Determinación de las estructuras cristalinas del receptor 5-HT2C en complejo con ergotamina y ritanserina.
- Las posiciones de unión ligando-receptor analizadas en alta resolución (3,0 Å y 2,7 Å).
- Investigó los mecanismos estructurales subyacentes al reconocimiento de los receptores y los efectos farmacológicos opuestos.
Principales resultados:
- Se resolvieron dos estructuras distintas del receptor 5-HT2C unidas a un agonista promiscuo (ergotamina) y un agonista inverso selectivo (ritanserina).
- Proporcionó un análisis detallado de las posturas de unión, revelando las interacciones clave que rigen el reconocimiento del receptor.
- Se ofrecieron explicaciones mecanicistas para las diferentes acciones farmacológicas de los ligandos unidos.
Conclusiones:
- Los conocimientos estructurales sobre las interacciones ligando-GPCR pueden explicar la polifarmacología.
- La comprensión de los patrones de unión característicos facilita el diseño de fármacos dirigidos a múltiples GPCR.
- Este trabajo sienta las bases para el diseño de nuevas terapias con perfiles polifarmacológicos adaptados.
Palabras clave:
GPCR y sus derivadosestructuras de cristalLa ergotamina también tiene un efecto secundario.polifarmacologíaRitancerina y sus derivadosSelectividadEl receptor de la serotonina 2CMás Videos Relacionados
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