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Evaluación de las reactividades de la lisina y la cisteína para el diseño de inhibidores de la cinasa covalente
Ruibin Liu1, Zhi Yue1, Cheng-Chieh Tsai1
1Department of Pharmaceutical Sciences , School of Pharmacy, University of Maryland , Baltimore , Maryland 21201 , United States.
Journal of the American Chemical Society
|April 5, 2019
Resumen
Los inhibidores covalentes dirigidos a la lisina ofrecen una nueva estrategia más allá de los medicamentos basados en cisteína, abordando limitaciones como la resistencia a los medicamentos. Este estudio identifica las lisinas reactivas en las quinasas, acelerando el descubrimiento de inhibidores covalentes racionales.
Área de la Ciencia:
- La bioquímica
- Química medicinal
- Biología computacional
Sus antecedentes:
- El diseño de inhibidores covalentes dirigidos es cada vez más importante.
- La orientación a la cisteína es común, pero limitada por la baja abundancia y resistencia.
- Las sondas dirigidas a la lisina inspiran la exploración de la reactividad de la lisina.
Objetivo del estudio:
- Investigar la prevalencia de las lisinas catalíticas nucleófilas (reactivas) en las quinasas humanas.
- Desarrollar una nueva estrategia para el diseño de inhibidores selectivos de la cinasa covalente dirigidos a la lisina.
- Evaluar el potencial de una nueva herramienta de predicción de pKa para identificar residuos reactivos.
Principales métodos:
- Utilizó una herramienta de predicción de pKa basada en la dinámica molecular de pH constante continua.
- Analizó las estructuras cristalinas publicadas del quinoma humano.
- Reactividad de la lisina predicha retrospectivamente y prospectivamente en las conformaciones específicas de la quinasa (DFG-out/αC-out).
Principales resultados:
- Se predijo que las lisinas catalíticas serían nucleófilas en conformaciones específicas de quinasa.
- Se identificaron otras lisinas y cisteinas reactivas en varias ubicaciones de la quinasa.
- Las lisinas y las cisteinas pueden existir en estados neutros y cargados a pH fisiológico, desafiando las suposiciones computacionales actuales.
Conclusiones:
- Propuso una nueva estrategia para diseñar inhibidores selectivos de la cinasa covalente dirigidos a la lisina mediante la modificación de inhibidores reversibles de tipo II.
- La herramienta de predicción de pKa desarrollada puede acelerar el descubrimiento racional de inhibidores covalentes.
- Los hallazgos sobre los estados de protonación de lisina y cisteína pueden alterar los estudios de quinasa computacional.
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