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Drug discovery and development with cryo-electron microscopy
Successful outcomes in structure-based drug design are not always a given. For instance, structures of membrane proteins or large macromolecular complexes often cannot be obtained quickly enough with crystallography or NMR to impact the drug design process. Despite the fact that membrane proteins account for over 60% of drug targets, they make up only 2% of existing crystal structures. This means that drug discovery is largely being performed without structure-based insights as part of a researcher’s toolbox.
With an ongoing pressure to reduce the time-to-market of new drugs, cryo-electron microscopy (cryo-EM) can help you take greater advantage of rational drug design and the observation of structure-activity relationships. This minimizes the number of compounds that must be synthesized and assayed, giving you highly efficient drug candidates in fewer iterations.
Recent technological breakthroughs have made cryo-EM the method of choice for the structural determination of large protein complexes, GPCRs, ion channels, and antibody complexes. The achievable resolution, throughput, and ease of use of cryo-electron microscopy have improved tremendously, and the number of cryo-EM publications is increasing with every month.
Cryo-EM for a wide range of targets
Whether you are a structural biologist, modeler, medicinal chemist, or pharmacologist, cryo-EM allows you to visualize molecules across a range of sizes and helps you obtain time-critical insights for your drug discovery project. Below are just a few of the potential drug targets that can be investigated with cryo-electron microscopy.
Cryo-EM is a proven and broadly applicable structure-based drug-design solution for G protein-coupled receptors (GPCRs). Cryo-electron microscopy allows you to identify active-state structures, revealing the binding site early in the drug discovery process and providing insight into Gs- and Gi-based specificity.
Ion channels
The near-native structures that can be determined with cryo-EM bring ion channels into the realm of structure-based drug design. Multiple conformations can be found for one specimen and can give insight into the channel’s dynamics or mode of action.
Antibodies
Even at low resolution, cryo-electron microscopy can identify (non-overlapping) epitopes, exploit synergistic effects by creating dual specific antibodies, or follow polyclonal response over time.
E3-ligases
Proteolysis targeting molecules (e.g. PROTACs) make undruggable targets druggable. With cryo-EM, you do not need to test linkers in the dark. Instead, you are able to directly observe the preferred orientations of your protein in complex with the E3 ligase.
Viruses
Knowing the quaternary structure of the viral epitope helps to inform vaccine design. For antivirals, both the capsid as well as non-structural viral proteins have been studied with cryo-EM.
Accelerating drug design with Cryo-EM
Cryo-EM techniques, such as single particle analysis and microcrystal electron diffraction (MicroED), are specifically designed for the structural analysis of proteins and small molecules. Cryo-EM allows you to visualize drug-target complexes at high resolution, giving key insight into the interactions of small molecules or large macromolecular assemblies. With single particle analysis, you can determine near-atomic-level molecular structures, guiding compound design from hit to lead and beyond. Cryo-EM excels at exposing the structure of biologics as well, providing critical information for everything from therapeutic antibody epitope mapping to increasingly large biopharmaceuticals.
Single particle analysis – protein structure without crystals
Single particle analysis has matured rapidly in the last few years, enabling structure-based drug design for a variety of complex systems, particularly membrane-proteins such as the GABAA receptor, TRP channels and GPCRs. Multiple research groups across the globe have successfully and repeatably obtained structures for their receptors of interest at high resolution.
With single particle analysis, multiple conformations can be observed in one sample, and even enumerated, because the protein/RNA samples are not limited by crystal contacts.
Our single particle analysis workflow ensures a smooth pathway from sample preparation to image acquisition and data processing. It integrates hardware with dedicated, automated sample-screening software to optimize biochemistry and vitrification parameters. Thermo Scientific cryo-transmission electron microscopes (cryo-TEMs) allow you to reliably produce 3D structures at near-atomic resolution.
MicroED – structural chemistry with electrons
MicroED is a single-crystal diffraction technique performed in a cryo-electron microscope that uses electrons instead of X-rays. The stronger interaction of electrons enables you to obtain a solvable structure from mere nanocrystals of your compound. Early MicroED studies have also shown a potential time-to-structure of just a few hours. This opens unheard of avenues of structural characterization for natural products, precious ligands, and metabolites, and may even enable polymorph identification.
Getting started with cryo-EM
Starting a cryo-EM facility can be a daunting task, but Thermo Fisher Scientific is determined to make the process as easy as possible. We will be with you every step of the way, from flexible financing options, to building planning, to initial sample testing and installation. Our goal is to get you up and running as quickly and efficiently as possible. You can also take advantage of fee-for-service providers, cryo-EM training, and more.
View the latest publications
It’s time to invest in cryo-EM today. Early cryo-EM adopters in the pharma industry already see its benefits. Find out why pharmaceutical leaders around the globe have invested in cryo-EM for drug discovery and learn how their motivations may align with your goals.
Increase your cryo-EM knowledge
Your lab personnel can quickly turn into cryo-EM experts by watching our online Cryo-EM University videos and with practical training from our dedicated application specialists. This exciting free course, created in collaboration with Professor Grant Jensen of Caltech University, combines online instruction with practical training to transform your personnel into cryo-electron microscopists. Learn a range of cryo-EM essentials, including step-by-step single particle analysis (SPA) instructions, expert demonstrations, and theoretical lessons, all available at your pace, wherever you want.
Cryo-EM? We have an app for that.
Our instruments’ tailor-made user interface makes operation an intuitive process, especially when combined with our easy-to-use app. This Scientific Workflows app guides you through the cryo-EM single-particle analysis workflow and offers advanced calculations like recommended data acquisition magnification and estimated acquisition time. It also contains step-by-step guides tailored to a given set of system configurations and sample/grid characteristics. If more assistance is required, applications experts are available for on-site support and training, ensuring you are ready to perform your research with a high level of confidence in your results.
Download the free app:
ROI calculator
Cryo-EM's ability to solve complex structures of the most challenging drug targets in less than months means that you can start seeing payoffs in your drug discovery process purely based on efficiency gain only. By using our cryo-EM ROI calculator, you can determine how soon cryo-EM can begin providing you with a tangible return on your investment (ROI).
Financial resources
We provide a variety of ways to meet your financial needs, including assistance with leasing and financing options. Avoid unexpected expenses by letting us help you properly plan for building and/or remodeling, determine IT infrastructure expenditures and operational costs, including personnel needs, power consumption, and data storage.
Planning and building advice
We are experts in creating cryo-EM labs. Supporting more than 100 high-end cryo-EM facilities around the world, we offer unparalleled knowledge and expertise. We will perform a site survey to make sure your site meets all room readiness requirements (including vibrations, magnetic fields, temperature stability, and humidity control) prior to installation. We will provide advice on IT infrastructure and resources required to handle big data, environmental conditions needed for the facility, and we will help you to determine what auxiliary lab equipment you might need. Our expertise and support are designed to get you up and running quickly.
Setting up for ongoing success
From day one to year one and beyond, you can rely on our expertise to support your investment and research. Our highly knowledgeable cryo-EM application specialists can assist with everything from sample preparation to data processing. Our Cryo-EM University combines online instruction with practical training to transform your lab personnel into a qualified team of cryo-electron microscopists. You can rely on us, a cryo-EM leader currently supporting more than 100 systems worldwide, for long term ongoing support.
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Neurodegenerative Disease Research
Cryo-EM can determine the structural features of protein aggregates implicated in neurodegenerative diseases, allowing scientists to address how they form, interact with the cellular environment, and alter brain function.
Proteins Analysis
Cryo-electron microscopy provides near-atomic resolution 3D protein structure. It can determine structural information for complexes and crystallization-resistant samples, as well as vital cellular context.
Biopharmaceutical Research
Structural drug discovery is enabled by cryo-electron microscopy, as the method provides near-atomic-resolution detail for small molecules and protein biologics in their fully hydrated state.
Virus Analysis
Cryo-EM enables the 3D structural visualization of virus particles, and the antigen-antibody interface, at near-atomic resolutions. A virus’s inherent structural symmetry makes it the ideal target for cryo-EM analysis.
Single Particle Analysis
Single particle analysis (SPA) is a cryo-electron microscopy technique that enables structural characterization at near-atomic resolutions, unraveling dynamic biological processes and the structure of biomolecular complexes/assemblies.
MicroED
MicroED is an exciting new technique with applications in the structural determination of small molecules and protein. With this method, atomic details can be extracted from individual nanocrystals (<200 nm in size), even in a heterogeneous mixture.
Single Particle Analysis
Single particle analysis (SPA) is a cryo-electron microscopy technique that enables structural characterization at near-atomic resolutions, unraveling dynamic biological processes and the structure of biomolecular complexes/assemblies.
MicroED
MicroED is an exciting new technique with applications in the structural determination of small molecules and protein. With this method, atomic details can be extracted from individual nanocrystals (<200 nm in size), even in a heterogeneous mixture.
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Want to know how cryo-EM can help you? Learn about the latest trends and come and chat with us at one of our booths.
| Date | Event |
| March 27-28, 2023 | 7th RSC-BMCS / SCI symposium on Ion channels as Therapeutic Targets |
| March 28-30, 2023 | Targeted Protein Degradation Europe |
| April 3-6, 2023 | World Vaccine Congress 2023 |
| April 10-13, 2023 | Drug Discovery Chemistry |
| April 26-28, 2023 | 9th NovAliX Conference |
| April 25-27, 2023 | CCP-EM Spring Symposium |
| May 9-10, 2023 | Kinase 2023: 10th SCI/RSC Symposium on Kinase Inhibitor Design |
| May 15-19, 2023 | PEGS Boston summit |
| June 6 - 8, 2023 | Antibody Engineering & Therapeutics Europe |
| June 7-9, 2023 | Hungary Biopharma Conference |
| June 11-16, 2023 | Gordon Research Conference - Progressive Technologies and Approaches Revealing Novel GPCR Biology and Drug Development Potential |
| June 13-16, 2023 | 3rd RSC Anglo-Nordic Medicinal Chemistry symposium |
| July 7-11, 2023 | American Crystallographic Association (ACA) Annual meeting |
| September 18-21, 2023 | Cell & Gene Therapy Manufacturing & Commercialization US |
| November 12–14, 2023 | Protein Structure Determination in Industry |
| December 13-16, 2023 | Antibody Engineering & Therapeutics US |
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