Activity-directed synthesis toolkit

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Activity-directed synthesis (ADS) is a novel discovery approach in which bioactive small molecules emerge in parallel with an associated synthetic route. The approach deliberately exploits reactions with many possible outcomes. Reaction arrays are performed in plate-based format, and the crude product mixtures are assayed for biological activity. Promising reactions then inform the design of reaction arrays in subsequent rounds. Finally, optimised reactions are scaled up, and the bioactive products are purified, structurally elucidated and functionally characterised. This iCASE project (in collaboration with GSK) will focus on expansion of the reaction toolkit for ADS to enable scaffold hopping. The new chemical tools will be exploited in the ADS of small molecule modulators of exemplar protein targets. The project focuses on the development of a new chemical approach to drive ligand discovery, and aligns with the EPSRC's chemical biology research area.