Interfacial inhibitors

Targeting macromolecular interface is a general mechanism by which natural products inactivate macromolecular complexes by stabilizing normally transient intermediates. Demonstrating interfacial inhibition mechanism ultimately relies on the resolution of drug-macromolecule structures. This review focuses on medicinal drugs that trap protein–DNA complexes by binding at protein–DNA interfaces. It provides proof-of-concept and detailed structural and mechanistic examples for topoisomerase inhibitors and HIV integrase inhibitors. Additional examples of recent interfacial inhibitors for protein–DNA interfaces are provided, as well as prospects for targeting previously ‘undruggable’ targets including transcription, replication and chromatin remodeling complexes. References and discussion are included for interfacial inhibitors of protein–protein interfaces.

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