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Enfoque quimioinformático flexible basado en el andamio para el diseño de fármacos polifarmacológicos

Zhangcheng Chen¹, Jing Yu¹, Huan Wang²

¹Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.

|March 29, 2024

Resumen

El diseño de fármacos polifarmacológicos para trastornos del sistema nervioso central (SNC) es un desafío. Un nuevo enfoque de quimioinformática flexible basado en el andamio (FSCA) permite el diseño racional de fármacos mediante la utilización de posturas de unión específicas para la participación de múltiples objetivos.

Área de la Ciencia:

Química medicinal
La neurociencia
Química computacional

Sus antecedentes:

Los tratamientos para trastornos complejos del sistema nervioso central (SNC) requieren fármacos con polifarmacología y multifuncionalidad.
El diseño de fármacos multi-objetivo sigue siendo un desafío importante en la química medicinal.

Objetivo del estudio:

Presentar un nuevo enfoque de quimioinformática basado en andamios flexibles (FSCA) para el diseño racional de fármacos polifarmacológicos.
Demostrar la aplicación de FSCA utilizando un nuevo compuesto dirigido a los receptores 5-HT2A y 5-HT1A.

Principales métodos:

El FSCA implica el montaje de un andamio flexible a diferentes receptores utilizando posturas de unión distintas.
El análisis de las estructuras de los receptores aminérgicos identificó motivos clave: "filtro agonista" y "conformador".
El compuesto IHCH-7179 fue diseñado utilizando FSCA, adoptando diferentes posiciones de unión en los receptores 5-HT2A y 5-HT1A.

Principales resultados:

IHCH-7179 actuó como antagonista en los receptores 5-HT2A y como agonista en los receptores 5-HT1A.
IHCH-7179 demostró eficacia en el alivio de los déficits cognitivos y los síntomas psicoactivos en modelos de ratón.
Los motivos identificados predicen la posición de unión del ligando y la actividad en los receptores aminérgicos.

Conclusiones:

La FSCA proporciona una estrategia racional para el diseño de fármacos polifarmacológicos.
Los motivos identificados son cruciales para predecir el comportamiento del ligando en los receptores aminérgicos.
FSCA puede extenderse para diseñar ligandos polifarmacológicos para otros receptores diana.

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