Pommier Yves, Cherfils Jacqueline
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA.
Trends Pharmacol Sci. 2005 Mar;26(3):138-45. doi: 10.1016/j.tips.2005.01.008.
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.
自然界干扰分子相互作用的策略之一，是将处于过渡状态的大分子与其伙伴困在无法完成其生物学功能的死端复合物中。我们将这种抑制类型称为“界面抑制”，天然抑制剂布雷菲德菌素A（BFA）和喜树碱（CPT）就体现了这一点，它们的作用模式已在结构研究中得到充分阐明。在BFA的情况下，界面抑制发生在蛋白质-蛋白质界面；在CPT的情况下，界面抑制发生在蛋白质-DNA界面。在这两种系统中，药物利用了大分子复合物产生的瞬态结构和能量条件，这些条件产生了药物结合的“热点”。除了这些例子外，一些天然化合物，如福斯可林、微管蛋白抑制剂和免疫亲和素，也靶向蛋白质界面。我们认为，界面抑制是发现干扰大分子复合物药物的一种范例。
