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.
Highlights
Dynamic combinatorial chemistry (DCC) has proven its potential in drug discovery speeding the identification of modulators of biological targets
Huc and Lehn reported the use of carbonic anhydrase as a template proving its inhibition by a dynamic combinatorial library (DCL) of imines created in situ[6]
The Neuronal Calcium Sensor 1 (NCS-1) is a high-affinity Ca2+-binding protein predominantly expressed in neurons[11,12]
Summary
Dynamic combinatorial chemistry (DCC) has proven its potential in drug discovery speeding the identification of modulators of biological targets. 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. Sanders and Lehn groups reported the concept of Dynamic Combinatorial Chemistry (DCC) in the mid-1990s1,2. DCC systems that employ a protein to direct assemblies of small molecules at dynamic equilibrium are highly interesting. On protein-directed DCC experiments, one designs the system rather than the molecule allowing the protein to find its best ligand in situ[8,9,10].
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