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Drug Discovery


Cryo-EM accelerates drug discovery by


delivering previously intractable structural insights


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.


C


ryo-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 reso- nance (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 diffi- cult to work with. This method reveals detailed structural features of targets, ligands and their interactions at the atomic level, reducing the devel- opment time and guesswork of lead compound design. Additionally, by capturing a series of intermedi-


ate states from a reaction mixture, ‘time-resolved’ EM is possible, providing structural information over the course of a reaction.


Drug Discovery World Winter 2019/20 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 solu- tions 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 compu- tational power. The acquisition of such models enables faster lead discovery and better lead opti- misation. This article is intended to introduce you to the


By Hans Raaijmakers, Dr Mazdak Radjainia, Dr Hervé-William Remigy and Aleksandar Stefanovic


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