NovAliX, Illkirch, France.
RiboStruct, Ostwald, France.
Nat Rev Drug Discov. 2018 Jul;17(7):471-492. doi: 10.1038/nrd.2018.77. Epub 2018 Jun 8.
Cryo-electron microscopy (cryo-EM) of non-crystalline single particles is a biophysical technique that can be used to determine the structure of biological macromolecules and assemblies. Historically, its potential for application in drug discovery has been heavily limited by two issues: the minimum size of the structures it can be used to study and the resolution of the images. However, recent technological advances - including the development of direct electron detectors and more effective computational image analysis techniques - are revolutionizing the utility of cryo-EM, leading to a burst of high-resolution structures of large macromolecular assemblies. These advances have raised hopes that single-particle cryo-EM might soon become an important tool for drug discovery, particularly if they could enable structural determination for 'intractable' targets that are still not accessible to X-ray crystallographic analysis. This article describes the recent advances in the field and critically assesses their relevance for drug discovery as well as discussing at what stages of the drug discovery pipeline cryo-EM can be useful today and what to expect in the near future.
冷冻电子显微镜（cryo-EM）技术可用于分析非晶体单颗粒，是一种生物物理技术，可用于确定生物大分子和复合物的结构。从历史上看，其在药物发现方面的应用受到两个问题的严重限制：其可以用于研究的结构的最小尺寸和图像的分辨率。然而，最近的技术进步——包括直接电子探测器的发展和更有效的计算图像分析技术——正在彻底改变 cryo-EM 的实用性，导致大量大分子复合物的高分辨率结构的爆发。这些进展使人们希望单颗粒 cryo-EM 可能很快成为药物发现的重要工具，特别是如果它们能够实现仍然无法通过 X 射线晶体学分析获得的“棘手”目标的结构测定。本文描述了该领域的最新进展，并批判性地评估了它们在药物发现中的相关性，同时还讨论了 cryo-EM 在药物发现管道的哪个阶段目前有用，以及在不久的将来可以期待什么。
