Department of Computational and Systems Biology, University of Pittsburh, Pittsburgh, PA 15260, USA.
Curr Top Med Chem. 2011;11(3):248-57. doi: 10.2174/156802611794072632.
Protein-protein interactions are involved in most of the essential processes that occur in living organisms from cell motility to DNA replication, which makes them interesting targets for drug discovery. However, due to the lack of deep pockets, and the large contact surfaces involved in these interactions, they are considered challenging targets and have been often times dismissed as "undruggable". Nonetheless, significant efforts in pharmaceutical and academic laboratories have been devoted to finding ways to exploit protein-protein interactions as drug targets. This article provides an overview of the principles underlying the main general strategies for discovering small-molecule modulators of protein-protein interactions, namely: high-throughput screening, fragment-based drug discovery, peptide-based drug discovery, protein secondary structure mimetics, and computer-aided drug discovery. In addition, examples of successful discovery of modulators of protein-protein interactions are discussed for each of those strategies.
蛋白质-蛋白质相互作用涉及到生物体中从细胞运动到 DNA 复制等大多数基本过程，这使得它们成为药物发现的有趣靶点。然而，由于缺乏雄厚的资金，以及这些相互作用涉及的大接触表面，它们被认为是具有挑战性的靶点，并且经常被视为“不可成药”。尽管如此，制药和学术实验室仍在努力寻找利用蛋白质-蛋白质相互作用作为药物靶点的方法。本文概述了发现小分子蛋白质-蛋白质相互作用调节剂的主要一般策略的原理，即：高通量筛选、基于片段的药物发现、基于肽的药物发现、蛋白质二级结构模拟物和计算机辅助药物发现。此外，还讨论了每种策略下成功发现蛋白质-蛋白质相互作用调节剂的例子。
