Applications and prospects of cryo-EM in drug discovery  

作　　者：Kong-Fu Zhu Chuang Yuan Yong-Ming Du Kai-Lei Sun Xiao-Kang Zhang Horst Vogel Xu-Dong Jia Yuan-Zhu Gao Qin-Fen Zhang Da-Ping Wang Hua-Wei Zhang 

机构地区：[1]Department of Biomedical Engineering,Southern University of Science and Technology,Shenzhen 518055,Guangdong,China [2]Department of Biochemistry and Molecular Biology,School of Basic Medical Sciences,Peking University,Beijing 100191,China [3]Department of Structural Biology,St.Jude Children’s Research Hospital,Memphis,TN 38105,USA [4]Center for Protein Science and Crystallography,School of Life Sciences,Faculty of Science,Chinese University of Hong Kong,Hong Kong 999077,China [5]Interdisciplinary Center for Brain Information,the Brain Cognition and Brain Disease Institute,Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences,Shenzhen 518055,Guangdong,China [6]Faculty of Life and Health Sciences,Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences,Shenzhen 518055,Guangdong,China [7]Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions,Shenzhen 518055,Guangdong,China [8]Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences,Shenzhen 518055,Guangdong,China [9]State Key Lab for Biocontrol,School of Life Sciences,Sun Yat-Sen University,Guangzhou 510275,China [10]Cryo‑EM Facility Center,Southern University of Science and Technology,Shenzhen 518055,Guangdong,China [11]Department of Orthopedics,Shenzhen Intelligent Orthopaedics and Biomedical Innovation Platform,Guangdong Provincial Research Center for Artifcial Intelligence and Digital Orthopedic Technology,Shenzhen Second People’s Hospital,The First Affiliated Hospital of Shenzhen University,Shenzhen 518000,Guangdong,China [12]Guangdong Provincial Key Laboratory of Advanced Biomaterials,Southern University of Science and Technology,Shenzhen 518055,Guangdong,China

出　　处：《Military Medical Research》2023年第6期848-861,共14页军事医学研究（英文版）

基　　金：funded by the National Natural Science Foundation of China (NSFC, 31900046, 81972085, 82172465 and 32161133022);the Guangdong Provincial Key Laboratory of Advanced Biomaterials (2022B1212010003);the National Science and Technology Innovation 2030 Major Program (2022ZD0211900);the Shenzhen Key Laboratory of Computer Aided Drug Discovery (ZDSYS20201230165400001);the Chinese Academy of Science President’s International Fellowship Initiative (PIFI)(2020FSB0003);the Guangdong Retired Expert (granted by Guangdong Province);the Shenzhen Pengcheng Scientist;NSFC-SNSF Funding (32161133022);Alpha Mol&SIAT Joint Laboratory;Shenzhen Government Top-talent Working Funding and Guangdong Province Academician Work Funding。

摘　　要：Drug discovery is a crucial part of human healthcare and has dramatically benefited human lifespan and life quality in recent centuries, however, it is usually time-and effort-consuming. Structural biology has been demonstrated as a powerful tool to accelerate drug development. Among different techniques, cryo-electron microscopy(cryo-EM) is emerging as the mainstream of structure determination of biomacromolecules in the past decade and has received increasing attention from the pharmaceutical industry. Although cryo-EM still has limitations in resolution, speed and throughput, a growing number of innovative drugs are being developed with the help of cryo-EM. Here, we aim to provide an overview of how cryo-EM techniques are applied to facilitate drug discovery. The development and typical workflow of cryo-EM technique will be briefly introduced, followed by its specific applications in structure-based drug design, fragment-based drug discovery, proteolysis targeting chimeras, antibody drug development and drug repurposing. Besides cryo-EM, drug discovery innovation usually involves other state-of-the-art techniques such as artificial intelligence(AI), which is increasingly active in diverse areas. The combination of cryo-EM and AI provides an opportunity to minimize limitations of cryo-EM such as automation, throughput and interpretation of mediumresolution maps, and tends to be the new direction of future development of cryo-EM. The rapid development of cryo-EM will make it as an indispensable part of modern drug discovery.

关 键 词：Cryo-electron microscopy(cryo-EM) Drug discovery Structure-based drug design Fragment-based drug discovery Proteolysis targeting chimeras Drug repurposing Artificial intelligence(AI) 

分 类 号：R318.52[医药卫生—生物医学工程]