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Modelado preciso de las preferencias conformacionales de los nucleósidos

Mihai Burai Patrascu¹, Elise Malek-Adamian¹, Masad J Damha¹

¹Department of Chemistry, McGill University , 801 Sherbrooke Street West, Montreal, Quebec H3A 0B8, Canada.

Journal of the American Chemical Society

|September 14, 2017

Resumen

Comprender la conformación de los nucleósidos es clave para el diseño de fármacos. Las simulaciones computacionales predicen con precisión el arrugamiento del azúcar en los nucleósidos modificados, lo que ayuda al desarrollo de terapias más efectivas.

Área de la Ciencia:

Bioquímica y Química Medicinal
Química computacional y modelado molecular

Sus antecedentes:

El azúcar de los nucleósidos influye en la estructura de los ácidos nucleicos y la función biológica.
La flexibilidad conformacional de los análogos de nucleósidos afecta la eficacia del fármaco, la incorporación del ADN y la escisión.
El desarrollo de análogos de nucleósidos con conformaciones específicas es crucial para mejorar las propiedades de los medicamentos.

Objetivo del estudio:

Predecir de forma computacional las preferencias conformacionales del azúcar de los nucleósidos modificados químicamente en solución.
Proporcionar información sobre cómo los sustituyentes afectan la conformación de los nucleósidos.
Ayudar en el diseño racional de nuevas terapias basadas en nucleósidos.

Principales métodos:

Simulaciones híbridas de mecánica cuántica y mecánica molecular.
Técnicas de muestreo general para explorar paisajes conformacionales.
Análisis del enlace orbital natural (NBO) para elucidar los efectos electrónicos.

Principales resultados:

Predicción precisa de las preferencias conformacionales del azúcar para los nucleósidos modificados.
Identificación de los sustituyentes clave que influyen en la estabilidad conformacional.
Correlación entre la conformación y la actividad biológica potencial.

Conclusiones:

El muestreo computarizado QM/MM es un método fiable para predecir la conformación de los nucleósidos.
Comprender los efectos de los sustituyentes en la conformación puede guiar el diseño de fármacos.
Este enfoque facilita el desarrollo de fármacos mejorados basados en nucleósidos con mayor bioactividad y farmacocinética.

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