Sable Rushikesh, Jois Seetharama
Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA.
Molecules. 2015 Jun 23;20(6):11569-603. doi: 10.3390/molecules200611569.
Blocking protein-protein interactions (PPI) using small molecules or peptides modulates biochemical pathways and has therapeutic significance. PPI inhibition for designing drug-like molecules is a new area that has been explored extensively during the last decade. Considering the number of available PPI inhibitor databases and the limited number of 3D structures available for proteins, docking and scoring methods play a major role in designing PPI inhibitors as well as stabilizers. Docking methods are used in the design of PPI inhibitors at several stages of finding a lead compound, including modeling the protein complex, screening for hot spots on the protein-protein interaction interface and screening small molecules or peptides that bind to the PPI interface. There are three major challenges to the use of docking on the relatively flat surfaces of PPI. In this review we will provide some examples of the use of docking in PPI inhibitor design as well as its limitations. The combination of experimental and docking methods with improved scoring function has thus far resulted in few success stories of PPI inhibitors for therapeutic purposes. Docking algorithms used for PPI are in the early stages, however, and as more data are available docking will become a highly promising area in the design of PPI inhibitors or stabilizers.
使用小分子或肽阻断蛋白质 - 蛋白质相互作用（PPI）可调节生化途径并具有治疗意义。设计类药物分子的PPI抑制是过去十年中广泛探索的一个新领域。考虑到可用的PPI抑制剂数据库数量以及蛋白质可用的3D结构数量有限，对接和评分方法在设计PPI抑制剂以及稳定剂方面发挥着重要作用。对接方法在寻找先导化合物的几个阶段用于PPI抑制剂的设计，包括对蛋白质复合物进行建模、在蛋白质 - 蛋白质相互作用界面上筛选热点以及筛选与PPI界面结合的小分子或肽。在PPI相对平坦的表面上使用对接存在三个主要挑战。在本综述中，我们将提供一些在PPI抑制剂设计中使用对接的示例及其局限性。到目前为止，将实验和对接方法与改进的评分函数相结合，在用于治疗目的的PPI抑制剂方面取得的成功案例很少。然而，用于PPI的对接算法尚处于早期阶段，随着更多数据可用，对接将成为PPI抑制剂或稳定剂设计中一个非常有前景的领域。
