Insights into real-time chemical processes in a calcium sensor protein-directed dynamic library

Andrea Canal-Martín, Javier Sastre, María José Sánchez-Barrena (), Angeles Canales, Sara Baldominos, Naiara Pascual, Loreto Martínez-González, Dolores Molero, Encarnación Fernández-Valle Mª, Elena Sáez, Patricia Blanco-Gabella, Elena Gómez-Rubio, Sonsoles Martín-Santamaría, Almudena Sáiz, Alicia Mansilla (), F. Javier Cañada, Jesús Jiménez-Barbero, Ana Martínez and Ruth Pérez-Fernández ()
Additional contact information
Andrea Canal-Martín: Centro de Investigaciones Biológicas, CIB-CSIC
Javier Sastre: Centro de Investigaciones Biológicas, CIB-CSIC
María José Sánchez-Barrena: Instituto de Química Física Rocasolano, IQFR-CSIC
Angeles Canales: Universidad Complutense de Madrid
Sara Baldominos: Centro de Investigaciones Biológicas, CIB-CSIC
Naiara Pascual: Centro de Investigaciones Biológicas, CIB-CSIC
Loreto Martínez-González: Centro de Investigaciones Biológicas, CIB-CSIC
Dolores Molero: CAI de RMN, Universidad Complutense de Madrid
Encarnación Fernández-Valle Mª: CAI de RMN, Universidad Complutense de Madrid
Elena Sáez: CAI de RMN, Universidad Complutense de Madrid
Patricia Blanco-Gabella: Instituto de Química Física Rocasolano, IQFR-CSIC
Elena Gómez-Rubio: Centro de Investigaciones Biológicas, CIB-CSIC
Sonsoles Martín-Santamaría: Centro de Investigaciones Biológicas, CIB-CSIC
Almudena Sáiz: Instituto Ramón y Cajal de Investigación Sanitaria. Ctra. Colmenar Viejo, km. 9100
Alicia Mansilla: Instituto Ramón y Cajal de Investigación Sanitaria. Ctra. Colmenar Viejo, km. 9100
F. Javier Cañada: Centro de Investigaciones Biológicas, CIB-CSIC
Jesús Jiménez-Barbero: CIC bioGUNE
Ana Martínez: Centro de Investigaciones Biológicas, CIB-CSIC
Ruth Pérez-Fernández: Centro de Investigaciones Biológicas, CIB-CSIC

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract Dynamic combinatorial chemistry (DCC) has proven its potential in drug discovery speeding the identification of modulators of biological targets. However, the exchange chemistries typically take place under specific reaction conditions, with limited tools capable of operating under physiological parameters. Here we report a catalyzed protein-directed DCC working at low temperatures that allows the calcium sensor NCS-1 to find the best ligands in situ. Ultrafast NMR identifies the reaction intermediates of the acylhydrazone exchange, tracing the molecular assemblies and getting a real-time insight into the essence of DCC processes at physiological pH. Additionally, NMR, X-ray crystallography and computational methods are employed to elucidate structural and mechanistic aspects of the molecular recognition event. The DCC approach leads us to the identification of a compound stabilizing the NCS-1/Ric8a complex and whose therapeutic potential is proven in a Drosophila model of disease with synaptic alterations.

Date: 2019
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DOI: 10.1038/s41467-019-10627-w

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