文献类型：期刊文献

英文题名：State-of-the-art strategies for targeting protein-protein interactions by small-molecule inhibitors

作者：Sheng, Chunquan[1];Dong, Guoqiang[1];Miao, Zhenyuan[1];Zhang, Wannian[1];Wang, Wei[2,3,4]

机构：[1]Second Mil Med Univ, Sch Pharm, Dept Med Chem, Shanghai 200433, Peoples R China;[2]Univ New Mexico, Dept Chem & Chem Biol, Albuquerque, NM 87131 USA;[3]E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China;[4]E China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China

年份：2015

卷号：44

期号：22

起止页码：8238

外文期刊名：CHEMICAL SOCIETY REVIEWS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000364065800010)】；

基金：Financial support of this research by the 863 Hi-Tech Program of China (Grant 2014AA020525, C.-Q. S.), the National Basic Research Program of China (grant 2014CB541800, C.-Q. S.), the National Natural Science Foundation of China (Grant 81222044, C.-Q. S. and 21372073, W. W.), and the Shanghai "ShuGuang'' Project (grant 14SG33, C.-Q. S.) is acknowledged.

语种：英文

摘要：Targeting protein-protein interactions (PPIs) has emerged as a viable approach in modern drug discovery. However, the identification of small molecules enabling us to effectively interrupt their interactions presents significant challenges. In the recent past, significant advances have been made in the development of new biological and chemical strategies to facilitate the discovery process of small-molecule PPI inhibitors. This review aims to highlight the state-of-the-art technologies and the achievements made recently in this field. The "hot spots'' of PPIs have been proved to be critical for small molecules to bind. Three strategies including screening, designing, and synthetic approaches have been explored for discovering PPI inhibitors by targeting the "hot spots''. Although the classic high throughput screening approach can be used, fragment screening, fragment-based drug design and newly improved virtual screening are demonstrated to be more effective in the discovery of PPI inhibitors. In addition to screening approaches, design strategies including anchor-based and small molecule mimetics of secondary structures involved in PPIs have become powerful tools as well. Finally, constructing new chemically spaced libraries with high diversity and complexity is becoming an important area of interest for PPI inhibitors. The successful cases from the recent five year studies are used to illustrate how these approaches are implemented to uncover and optimize small molecule PPI inhibitors and notably some of them have become promising therapeutics.