Chapter 6: Function-driven Discovery of Bioactive Small Molecules

The discovery of bioactive small molecules is currently dominated by iterative cycles of design, synthesis, purification and evaluation. In stark contrast, the emergence of natural products is structure-blind, and is driven by functional benefit to the host organism. Two function-driven approaches for the discovery of bioactive small molecules have recently emerged: synthetic fermentation and activity-directed synthesis. In both cases, arrays of reactions are performed, and the crude product mixtures are directly screened for biological function. The most promising reactions can inform the design of subsequent reaction arrays and, hence, optimisation of the synthesis of bioactive products. Finally, the products are purified, structurally elucidated and functionally characterised. Although in their infancy, function-driven approaches may improve the efficiency of molecular discovery, and increase the range of functional chemotypes that may be discovered.