Fragment-based drug discovery using cryo-EM

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Cryo-EM maps can be used for structure-based drug design. • Cryo-EM can provide the throughput necessary to support fragment-based screening. • They present the first cryo-EM structure of the oncology target PKM2. • We discuss future developments that will enhance fragment-based drug discovery.

Recent advances in electron cryo-microscopy (cryo-EM) structure determination have pushed the resolutions obtainable by the method into the range widely considered to be of utility for drug discovery. Here, we review the use of cryo-EM in fragment-based drug discovery (FBDD) based on in-house method development. We demonstrate not only that cryo-EM can reveal details of the molecular interactions between fragments and a protein, but also that the current reproducibility, quality, and throughput are compatible with FBDD. We exemplify this using the test system β-galactosidase (Bgal) and the oncology target pyruvate kinase 2 (PKM2). 

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