Applications and prospects of cryo-EM in drug discovery.
Applications and prospects of cryo-EM in drug discovery.
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DOI：
10.1186/s40779-023-00446-y
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发表时间：
2023-03-06
影响因子：
21.1
通讯作者：
Zhang, Hua-Wei
中科院分区：
文献类型：
--
作者：
Zhu, Kong-Fu;Yuan, Chuang;Du, Yong-Ming;Sun, Kai-Lei;Zhang, Xiao-Kang;Vogel, Horst;Jia, Xu-Dong;Gao, Yuan-Zhu;Zhang, Qin-Fen;Wang, Da-Ping;Zhang, Hua-Wei
关键词：
药物发现是人类医疗保健的重要组成部分，近几个世纪来极大地改善了人类的寿命和生活质量，但通常耗时费力。结构生物学已被证明是加速药物开发的有力工具。在各种技术中，低温电子显微镜（cryo-EM）在过去的十年中逐渐成为生物大分子结构测定的主流，并受到制药行业越来越多的关注。尽管cryo-EM在分辨率、速度和通量方面仍有局限性，但越来越多的创新药物正在cryo-EM的帮助下开发。在这里，我们的目的是提供一个概述如何冷冻EM技术应用于促进药物发现。本文简要介绍了cryo-EM技术的发展和典型工作流程，以及cryo-EM技术在基于结构的药物设计、基于片段的药物发现、蛋白质水解靶向嵌合体、抗体药物开发和药物再利用等方面的具体应用。除了cryo-EM，药物发现创新通常涉及其他最先进的技术，如人工智能（AI），它在不同领域越来越活跃。cryo-EM和AI的结合为减少cryo-EM的局限性提供了机会，例如自动化，吞吐量和中等分辨率地图的解释，并倾向于成为cryo-EM未来发展的新方向。冷冻电镜的迅速发展将使其成为现代药物发现中不可缺少的一部分。
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 medium-resolution 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.