Interfacial inhibitors of protein-nucleic acid interactions.
This essay develops the paradigm of "Interfacial Inhibitors" (Pommier and Cherfils, TiPS, 2005, 28: 136) for inhibitory drugs beside orthosteric (competitive or non-competitive) and allosteric inhibitors. Interfacial inhibitors bind with high selectivity to a binding site involving two or more macromolecules within macromolecular complexes undergoing conformational changes. Interfacial binding traps (generally reversibly) a transition state of the complex, resulting in kinetic inactivation. The exemplary case of interfacial inhibitor of protein-DNA interface is camptothecin and its clinical derivatives. We will also provide examples generalizing the interfacial inhibitor concept to inhibitors of topoisomerase II (anthracyclines, ellipticines, epipodophyllotoxins), gyrase (quinolones, ciprofloxacin, norfloxacin), RNA polymerases (alpha-amanitin and actinomycin D), and ribosomes (antibiotics such as streptomycin, hygromycin B, tetracycline, kirromycin, fusidic acid, thiostrepton, and possibly cycloheximide). We discuss the implications of the interfacial inhibitor concept for drug discovery.
Pommier
Yves
Y
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Heath, Bethesda, Maryland 20892-4255, USA. pommier@nih.gov
Marchand
Christophe
C
D000818:Animals; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D009696:Nucleic Acids / Q000737:chemistry / Q000378:metabolism*; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors / Q000378:metabolism; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism; D059005:Topoisomerase II Inhibitors
D004268:DNA-Binding Proteins; D009696:Nucleic Acids; D059005:Topoisomerase II Inhibitors; D012319:RNA Polymerase II; D004250:DNA Topoisomerases, Type II