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

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.

Biomimetic selenocystine based dynamic combinatorial chemistry for thiol-disulfide exchange

“…However, the application of certain additives in biological environments is limited. The addition of a suitable catalyst 18 or additive was reported for acylhydrazone exchange to enable the exchange at neutral pH in 5 h even at low temperatures 19 . The possibility of conducting the thiol-disulfide exchange under a reasonable timeframe would benefit from its application in biotemplated-driven dynamic chemical systems and systems chemistry research [20][21][22][23][24] .…”

Protein-Directed Dynamic Combinatorial Chemistry: An Efficient Strategy in Drug Design

“…In general, at room temperature, the reversible exchange is more efficient reducing the equilibration time of the DCL, although examples have been reported where low temperatures were applied to preserve the protein stability. 5 …”

“…Comparative and noncomparative analysis can be applied to P-D DCLs ( Figure 7 ). A comparative analysis needs a blank reaction without the target, to run concurrent with a templated one such as HPLC-MS 5 , 12 , 19 and DSF. 16 In the noncomparative approach, the hits can be analyzed in complex with the target, and no amplification rate is calculated like in ligand-observed nuclear magnetic resonance techniques, 6 , 25 SEC-MS, 9 and nondenaturing MS. 26 In this approach, the absence of a blank DCL makes it difficult to check that the thermodynamic equilibrium has been reached.…”

Hit-optimization using target-directed dynamic combinatorial chemistry: development of inhibitors of the anti-infective target 1-deoxy-d-xylulose-5-phosphate synthase

“…Since the rst report of tdDCC by Lehn and coworkers, 1,2 it has emerged as a powerful tool to identify new ligands of biological targets. [3][4][5][6][7][8][9] This self-screening approach reduces the synthetic efforts given that only the amplied hits need to be synthesized. Ultimately, it results in acceleration of the discovery of hit compounds in the early stages of drug discovery.…”