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

By J. Renaud, A. Chari, C. Ciferri, Wen-ti Liu, H. Rémigy, H. Stark, C. Wiesmann. 2018

391 citations recorded by the source corpus.

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.

Subfields: Materials Chemistry, Molecular Biology, Structural Biology

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Citations in the corpus

GPCRdb in 2021: integrating GPCR sequence, structure and function (2020, background): “cryo-electron microscopy (cryo-EM) (6), deep mutational scanning (7), genome sequencing (8) and signal protein profiling (9,10).”
Rational design of ASCT2 inhibitors using an integrated experimental-computational approach (2021, background): “Recently, the combination of different sampling and refinement approaches with ligand docking has aided the design of small molecule ligands, particularly, for challenging membrane protein targets such as G proteincoupled receptors (GPCRs) and transient receptor potential (TRP) channels (18, 32, 44,”
Reconstructing continuous distributions of 3D protein structure from cryo-EM images (2019, background): “Despite these challenges, continuing advances in hardware and software have enabled structure determination at near-atomic resolution for rigid proteins (Kühlbrandt (2014); Scheres (2012b); Renaud et al. (2018); Li et al. (2013)).”
Synthon-based ligand discovery in virtual libraries of over 11 billion compounds (2021, methodology): “The affinities ( K i ) of the new compounds for rat CB 1 receptors and human CB 2 receptors were obtained using membrane preparations from rat brain or HEK293 cells, respectively, and [ 3 H]CP-55,940 as the radioligand, as previously described 42,43 .”
Computational approaches streamlining drug discovery (2023, background): “…structural revolution—from automation in crystallography 12 to microcrystallography 13,14 and most recently cryo-electron microscopy technology 15,16 —has made it possible to reveal 3D structures for the majority of clinically relevant targets, often in a state or molecular complex relevant to…”
A geometric deep learning approach to predict binding conformations of bioactive molecules (2021, methodology): “Each residual block starts by projecting the node and edge features (vh−1 i and e h−1 i,j , respectively) to a 32D vector using an MLP as shown in equations (5) and (6).”