Interfacial inhibition of macromolecular interactions: nature's paradigm for drug discovery

One of nature's strategies for interfering with molecular interactions is to trap macromolecules in transition states with their partners in dead-end complexes that are unable to complete their biological function. This type of inhibition, which we refer to as "interfacial inhibition", is illustrated by two natural inhibitors, brefeldin A (BFA) and camptothecin (CPT), whose modes of action have been elucidated fully in structural studies. Interfacial inhibition occurs at the protein-protein interface in the case of BFA and at the protein-DNA interface in the case of CPT. In both systems, the drugs take advantage of transient structural and energetic conditions created by the macromolecular complex, which give rise to "hot-spots" for drug binding. In addition to these examples, several natural compounds such as forskolin, tubulin inhibitors and immunophilins target protein interfaces. We propose that interfacial inhibition is a paradigm for the discovery of drugs that interfere with macromolecular complexes.