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Interfacial inhibition is a widespread molecular mechanism by which natural products, such as toxins, inactivate macromolecular complexes by trapping normally transient conformational intermediates. This mechanism is effectively harnessed for therapeutic purposes, primarily in the case of antibacterial and chemotherapeutic anticancer drugs. This chapter provides case studies for drugs targeting protein–DNA interfaces, such as topoisomerase inhibitors and HIV integrase inhibitors. Examples of interfacial inhibitors for protein–protein interfaces are also provided for gyrase, STING and Arp2–3 inhibitors. Interfacial inhibition offers prospects for targeting previously ‘undruggable’ targets, including transcription, replication and chromatin-remodelling complexes. From a discovery viewpoint, the interfacial inhibition principle establishes the value of natural-product screening, the importance of non-competitive inhibitors and the value of high-throughput assays based on enhancement of macromolecular complex formation rather than disruption.

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