Drug discovery in the era of cryo-electron microscopy

Structure-based drug discovery (SBDD) is an indispensable approach for the design and optimization of new therapeutic agents. Here, we highlight the rapid progress that has turned cryo‐electron microscopy (cryoEM) into an exceptional SBDD tool, and the wealth of new structural information it is providing for high-value pharmacological targets. We review key advantages of a technique that directly images vitrified biomolecules without the need for crystallization; both in terms of a broader array of systems that can be studied and the different forms of information it can provide, including heterogeneity and dynamics. We discuss near- and far-future developments, working in concert towards achieving the resolution and throughput necessary for cryoEM to make a widespread impact on the SBDD pipeline. CryoEM has recently obtained resolutions sufficient for informing SBDD.The use of cryoEM allows access to new types of structures for SBDD, such as transmembrane proteins and difficult-to-crystalize complexes.New computational tools combined with cryoEM data provide key data for understanding ligand–protein interactions.Advances in cryoEM are rapidly improving accessibility and throughput, including increased automation in both hardware and software, and technical advances to improve signal to noise ratios and speed.New computational tools are unharnessing the ability of cryoEM to capture intermediate and equilibrium states of ligand–protein complexes.