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

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Dynamic combinatorial chemistry (DCC) has proven its potential in drug discovery speedingthe identification of modulators of biological targets. However, the exchange chemistriestypically take place under specific reaction conditions, with limited tools capable of operatingunder physiological parameters. Here we report a catalyzed protein-directed DCC working atlow temperatures that allows the calcium sensor NCS-1 tofind the best ligands in situ.Ultrafast NMR identifies the reaction intermediates of the acylhydrazone exchange, tracingthe molecular assemblies and getting a real-time insight into the essence of DCC processesat physiological pH. Additionally, NMR, X-ray crystallography and computational methods areemployed 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/Ric8acomplex and whose therapeutic potential is proven in aDrosophilamodel of disease withsynaptic alterations.
This work was supported by differentfunding agencies: the Spanish Ministry of Economy and Competitiveness (MINECO)with Grants CTQ2015-69643-R (R.P.F), SAF2015-74507-JIN (A. Mansilla) andBIO2017-89523-R (M.J.S.-B.), and European Cooperation in Science and Technology(COST) action CMI304 Emergence and evolution of complex chemical systems (R.P.-F.),and a 2017 Leonardo Grant for Researchers and Cultural Creators from the BBVAFoundation (M.J.S.-B) and a 2018 CaixaImpulse program from La Caixa Foundation(A.Mansilla). M.J.S.-B. was supported by a Ramón y Cajal Contract RYC-2008-03449from MINECO.