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Optimización basada en la estructura de estabilizadores covalentes de moléculas pequeñas de la interacción
Markella Konstantinidou1, Emira J Visser2, Edmee Vandenboorn2
1Department of Pharmaceutical Chemistry and Small Molecule Discovery Center (SMDC), University of California, San Francisco, California 94143, United States.
Journal of the American Chemical Society
|September 7, 2023
Resumen
Los investigadores desarrollaron pegamentos moleculares selectivos para estabilizar las interacciones proteína-proteína (IPP), específicamente dirigidos al complejo 14-3-3σ/ERα. Este enfoque guiado por la estructura optimiza la potencia y la selectividad para el descubrimiento de fármacos.
Área de la Ciencia:
- Biología Química
- Descubrimiento de drogas
- Biología estructural
Sus antecedentes:
- La estabilización de las interacciones proteína-proteína (IPP) es una estrategia clave en el descubrimiento de fármacos.
- El desarrollo de pegamentos moleculares selectivos para IPP carece de optimización guiada por la estructura.
- Trabajos anteriores identificaron un fragmento de disulfuro que estabiliza 14-3-3σ con clientes como ERα y C-RAF.
Objetivo del estudio:
- Optimizar un fragmento no selectivo en estabilizadores de moléculas pequeñas selectivos y potentes para el complejo 14-3-3σ/ERα.
- Para demostrar la optimización guiada por la estructura para el desarrollo de pegamento molecular.
- Para lograr una alta potencia, cooperatividad y selectividad en estabilizadores de pequeñas moléculas.
Principales métodos:
- Diseño y optimización de fármacos basados en la estructura.
- Se utilizaron ensayos biofísicos ortogonales (espectrometría de masas, anisotropía de fluorescencia) para establecer la relación estructura-actividad.
- Se empleó la cristalografía de rayos X para dilucidar los modos de unión de 37 compuestos.
Principales resultados:
- Desarrollo de estabilizadores selectivos de moléculas pequeñas para el complejo 14-3-3σ/ERα, sin estabilización observada para 14-3-3σ/C-RAF.
- El estabilizador covalente optimizado 181 logró una potencia, cooperatividad y selectividad comparables a la de Fusicoccin-A.
- Las relaciones estructura-actividad y los modos de unión se determinaron mediante análisis cristalográficos y biofísicos.
Conclusiones:
- La optimización guiada por la estructura es crucial para desarrollar pegamentos moleculares selectivos y potentes.
- La orientación hacia residuos de interfaz específicos y la conformación de bloqueo mejora la eficacia del estabilizador.
- Este estudio pone de relieve la importancia de la estructura, la cinética y la cooperatividad en el diseño de pegamento molecular.
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