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.
Pommier
Yves
Y
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA. Pommier@nih.gov
Cherfils
Jacqueline
J
D000818:Animals; D015195:Drug Design; D004347:Drug Interactions / Q000502:physiology; D006801:Humans; D046911:Macromolecular Substances / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology
D046911:Macromolecular Substances; D004364:Pharmaceutical Preparations