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Diseño basado en la estructura de los ligandos selectivos beta del receptor de estrógeno

Eric S Manas¹, Rayomand J Unwalla, Zhang B Xu

¹Department of Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. manase@wyeth.com

Journal of the American Chemical Society

|November 19, 2004

Resumen

Optimizamos los ligandos selectivos del receptor beta de estrógenos (ERbeta) utilizando un diseño basado en la estructura. Las sutiles diferencias de bolsillo de unión produjeron más de 100 veces la selectividad de ERbeta, avanzando el desarrollo del modulador selectivo del receptor de estrógeno.

Área de la Ciencia:

Química Medicinal La Química Medicinal es un campo de estudio de la química medicinal.
Biología Estructural Biología estructural.
Química computacional es la química computacional.

Sus antecedentes:

Los receptores de estrógenos (RE) juegan un papel crítico en la fisiología y la enfermedad.
La orientación selectiva de ERalpha y ERbeta es crucial para la intervención terapéutica.
El desarrollo de ligandos selectivos para ERbeta sigue siendo un desafío debido a la alta homología de secuencia entre ERalpha y ERbeta.

Objetivo del estudio:

Presentar la optimización basada en la estructura de nuevos ligandos selectivos para ERbeta.
Para dilucidar las bases estructurales de la selectividad utilizando cristalografía de rayos X y modelado molecular.
Comprender el mecanismo de mejora de la selectividad a través de cálculos químicos cuánticos.

Principales métodos:

Diseño de fármacos basado en la estructura y optimización de los ligandos selectivos de ERbeta.
Cocristalografía de rayos X para determinar las estructuras complejas ligando-ERalfa y ligando-ERbeta.
Modelado molecular y cálculos químicos cuánticos para analizar las interacciones de unión y la selectividad.

Principales resultados:

Las estructuras cocristalinas revelaron interacciones clave que impulsan la selectividad.
El modelado molecular explotó con éxito diferencias sutiles en las cavidades de unión ERalpha y ERbeta.
Los ligandos optimizados lograron una selectividad >100 veces mayor para ERbeta sobre ERalpha en ensayos de unión.
Las sustituciones mínimas de residuos en el bolsillo de unión de ligando fueron suficientes para una alta selectividad.

Conclusiones:

El diseño basado en la estructura es efectivo para desarrollar ligandos ERbeta altamente selectivos.
La comprensión de las diferencias sutiles de los bolsillos de enlace es clave para lograr una orientación selectiva de ER.
Estos hallazgos proporcionan una base para el desarrollo de nuevas terapias dirigidas a las vías mediadas por ERbeta.

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