Cryo-EM in drug discovery: achievements, limitations and prospects

Abstract

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.

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Figure 1: Cryo-EM timeline.
Figure 2: Selected key events in the development of the three main biophysical methodologies for 3D structure determination of macromolecules for drug discovery.

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Correspondence to Jean-Paul Renaud or Ashwin Chari or Claudio Ciferri or Wen-ti Liu or Hervé-William Rémigy or Holger Stark or Christian Wiesmann.

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J.-P.R. is a co-founder and shareholder of NovAliX. H.-W.R. is employed by Thermo Fisher Scientific, which manufactures electron microscopes that are used for cryo-EM. A.C. and H.S. are co-founders and stakeholders in Proteoplex GmbH.

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Renaud, J., Chari, A., Ciferri, C. et al. Cryo-EM in drug discovery: achievements, limitations and prospects. Nat Rev Drug Discov 17, 471–492 (2018). https://doi.org/10.1038/nrd.2018.77

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