Che Ye, Brooks Bernard R, Marshall Garland R
Laboratory of Computational Biology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
J Comput Aided Mol Des. 2006 Feb;20(2):109-30. doi: 10.1007/s10822-006-9040-8. Epub 2006 Apr 19.
Protein-protein interactions are ubiquitous, essential to almost all known biological processes, and offer attractive opportunities for therapeutic intervention. Developing small molecules that modulate protein-protein interactions is challenging, owing to the large size of protein-complex interface, the lack of well-defined binding pockets, etc. We describe a general approach based on the "privileged-structure hypothesis" [Che, Ph.D. Thesis, Washington University, 2003] - that any organic templates capable of mimicking surfaces of protein-recognition motifs are potential privileged scaffolds as protein-complex antagonists--to address the challenges inherent in the discovery of small-molecule inhibitors of protein-protein interactions.
蛋白质-蛋白质相互作用无处不在，对几乎所有已知的生物过程都至关重要，并为治疗干预提供了诱人的机会。由于蛋白质复合物界面尺寸较大、缺乏明确的结合口袋等原因，开发能够调节蛋白质-蛋白质相互作用的小分子具有挑战性。我们描述了一种基于“特权结构假说”[Che，博士论文，华盛顿大学，2003年]的通用方法——即任何能够模拟蛋白质识别基序表面的有机模板作为蛋白质复合物拮抗剂都可能是潜在的特权支架——以应对在发现蛋白质-蛋白质相互作用小分子抑制剂过程中固有的挑战。
