Drug Discovery
Cryo-EM accelerates drug discovery by delivering previously intractable structural insights
Cryo-EM accelerates drug discovery by delivering previously intractable structural insights

Cryo-EM accelerates drug discovery by delivering previously intractable structural insights

By Hans Raaijmakers, et al.

Cryo-electron microscopy (cryo-EM), a powerful biophysical technique that can analyse molecular assemblies, is changing the paradigm in structure-based drug design.

As targets become more challenging, solving structures of drug target molecules or biologics becomes increasingly difficult. Cryo-EM empowers drug discovery teams to take advantage of rational drug design for many more major drug target classes, opening a pathway to best-in-class drugs.

Cryo-EM allows the structural analysis of protein complexes flash-frozen in their near native states. One can now directly visualise not just large macromolecules, but also smaller proteins complexes, including membrane proteins. This powerful technique can be used to complement traditional methods, such as X-ray crystallography (XRD) or nuclear magnetic resonance (NMR) for structure-based drug discovery.

Cryo-EM enables structural analysis of protein complexes, providing better insight into all classes of biomolecules, including proteins that are difficult to work with. This method reveals detailed structural features of targets, ligands and their interactions at the atomic level, reducing the development time and guesswork of lead compound design.

Additionally, by capturing a series of intermediate states from a reaction mixture, ‘time-resolved’ EM is possible, providing structural information over the course of a reaction.

Conformational analysis of these intermediates provides unique, physiologically-relevant details of disease mechanisms. Even intractable targets are laid bare by cryo-EM. You can now analyse sample amounts that are generally too small for other techniques. No crystallisation, concentrated solutions or epitope labelling are needed, meaning ion channels, transporters and receptors can now be analysed. Also, membrane protein complexes in their native lipid environment can now be observed, thanks to lipid nanodiscs combined with cryo-EM single particle analysis (SPA). Atomic models can be obtained with cryo-EM due to the combination of ultra-stable microscopes with automatic cryogenic sample handling, cameras that are fast and super sensitive, high-performance image processing procedures and modern computational power. The acquisition of such models enables faster lead discovery and better lead optimisation.

This article is intended to introduce you to the versatility of cryo-EM and to the variety of benefits made possible with this method. Based on the results of these applications, you can determine if the adoption of cryo-EM for your projects can lead to an increase in the number of valid results, thereby improving your rational design efforts.....

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