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Elucidación del mecanismo de acción compuesto mediante el análisis de la perturbación de la red

Jung Hoon Woo¹, Yishai Shimoni², Wan Seok Yang³

¹Department of Biomedical Informatics (DBMI), Columbia University, New York, NY 10032, USA.

|July 18, 2015

Resumen

Este estudio presenta un nuevo enfoque basado en la red para identificar el mecanismo de acción (MoA) de las moléculas pequeñas. El método revela de manera eficiente los objetivos e interacciones de los compuestos, lo que ayuda al descubrimiento de fármacos y a la evaluación de la toxicidad.

Área de la Ciencia:

Farmacología
Biología de sistemas
Biología computacional

Sus antecedentes:

La identificación del mecanismo de acción de los compuestos de pequeñas moléculas es crucial para la evaluación de la eficacia y la toxicidad de los fármacos.
Los métodos actuales son a menudo intensivos en mano de obra y se centran principalmente en objetivos de proteínas de alta afinidad.
Una comprensión completa del MoA en todo el genoma sigue siendo un desafío significativo en el desarrollo de medicamentos.

Objetivo del estudio:

Desarrollar y validar un nuevo enfoque basado en la red reguladora para la elucidación del MoA en todo el genoma.
Identificar las proteínas conocidas y nuevas involucradas en el compuesto MoA.
Descubrir semejanzas y mecanismos compuestos inesperados para drogas con MOA desconocido.

Principales métodos:

Utilizó un enfoque basado en la red reguladora que analiza la desregulación de la interacción molecular global después de la perturbación del compuesto.
Perfiles de perturbación celular aplicados para evaluar los efectos compuestos en las redes moleculares.
Se realizó una validación experimental para elucidar nuevas proteínas MoA.

Principales resultados:

El enfoque basado en la red identificó con éxito proteínas MoA establecidas para el 70% de los compuestos probados.
Se esclarecieron nuevas proteínas de MoA y posteriormente se validaron experimentalmente.
Altretamina, un fármaco contra el cáncer, fue identificado como un inhibidor de la actividad de reparación lipídica de la glutatión peroxidasa 4, revelando similitud con la sulfasalazina.

Conclusiones:

El análisis de la red reguladora ofrece una herramienta poderosa para dilucidar la molécula pequeña MoA en todo el genoma.
Este enfoque puede descubrir nuevos objetivos y mecanismos de medicamentos, mejorando el descubrimiento y desarrollo de medicamentos.
Los hallazgos ponen de relieve el potencial para identificar similitudes compuestas inesperadas y oportunidades de reutilización.

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