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Electron Microscopy

Drug Discovery Using Cryo-Electron Microscopy

Drug discovery using cryo-electron microscopy for rational drug design.


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

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

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

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

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.

Publications

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.

Read testimonials and publications ›

Cryo-EM University

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.

Enroll in Cryo-EM University ›

Cryo-EM App

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:

Cryo-EM access as a service

Cryo-EM access as a service

The ability to visualize your samples provides you with an unprecedent competitive advantage for your structure-based drug design projects. We believe that our technology should be accessible to every scientist, which is why we offer a range of cryo-EM services for companies of any size.

Learn more ›

ROI calculator

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).

Have your business case calculated ›

Financial resources

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.

Review available financing options ›

Planning and building advice

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.

Learn more from our in-depth planning guide ›

Setting up for ongoing success

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.

Learn about our cryo-EM support expertise ›

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Resources

Ask the Experts | June 30, 2021

Integrated gene-to-cryo-EM-structure workflow for challenging targets

Get answers to questions about using cryo-EM for challenging drug targets and learn more about incorporating the Proteros gene-to-cryo-EM-structure integrated workflow as part of a successful cryo-EM process.


Ask the Experts | April 1, 2021

Integrating cryo-EM into your existing drug development process

Ask the Experts session on integrating cryo-EM into your existing drug development process. Get answers to common questions like how and when to integrate, find out which samples are suitable for cryo-EM and when to choose that technology over traditional methods like crystallography and nuclear magnetic resonance, and learn more about your options for outsourcing cryo-EM. This session includes a short presentation from NanoImaging Services followed by our Q&A.


Cryo-EM in Drug Discovery | March 11, 2021

Cryo-EM in Drug Discovery - Accelerating Drug Design for Intractable Targets

Thought-provoking presentations by four keynote speakers. Dr. Corey Strickland, Merck, presents From Concept to Reality: Cryo-EM as an Integral Part of Drug Discovery and Development. Dr. Lionel Rougé, Genentech, shares his insights on Structural Characterization of Different TRPA1 Inhibitors. Dr. Kenneth Borelli. Schrödinger, speaks about Improving Protein-Ligand Modeling into Cryo-EM Data and the use of those Models in Drug Discovery Efforts. And Prof. Patrick Sexton, Monash University, explains the Use of Cryo-EM for GPCR Drug Discovery and Development.

Cryo-EM in Drug Discovery - Panel Discussion

Dr. Jeffrey Lengyel, Thermo Fisher Scientific, Dr. Benjamin Apker, Mitegen, Dr. Corey Strickland, Merck, and Dr. Denis Zeyer, Novalix, will elaborate their opinion on how cryo-EM technology accelerates drug design of intractable targets.

Ask the Experts | December 9, 2020

Enhanced automation for high throughput cryo-EM screening and data collection for drug design

Ask the Experts webinar highlighting recent advances in cryo-EM automation for increased productivity to provide structural insights for your drug discovery pipeline. Andreas Schenk, Novartis, and Ben Apker, MiTeGen, discuss how the state-of-the-art cryo-EM workflow automations compares to X-ray crystallography in terms throughput and resolution.

Cryo-EM in Drug Discovery Virtual Event | September 29, 2020

Latest scientific developments in cryo-electron microscopy and electron diffraction

Two keynote lectures from leaders in the field of cryo-EM and electron diffraction will present latest results and how these techniques enable them to push the boundaries of their pipeline and research projects.

Cryo-EM solution optimized for drug discovery

Learn more on our recently launched iSPA Workflow solution, specifically designed to accelerate the structure-based drug discovery process.

Round table discussion

Experts in the field will elaborate about their experiences with getting cryo-EM technology in-house and offer practical consideration for how to setup a successfully running cryo-EM workflow.

Ask the Experts | June 30, 2021

Integrated gene-to-cryo-EM-structure workflow for challenging targets

Get answers to questions about using cryo-EM for challenging drug targets and learn more about incorporating the Proteros gene-to-cryo-EM-structure integrated workflow as part of a successful cryo-EM process.


Ask the Experts | April 1, 2021

Integrating cryo-EM into your existing drug development process

Ask the Experts session on integrating cryo-EM into your existing drug development process. Get answers to common questions like how and when to integrate, find out which samples are suitable for cryo-EM and when to choose that technology over traditional methods like crystallography and nuclear magnetic resonance, and learn more about your options for outsourcing cryo-EM. This session includes a short presentation from NanoImaging Services followed by our Q&A.


Cryo-EM in Drug Discovery | March 11, 2021

Cryo-EM in Drug Discovery - Accelerating Drug Design for Intractable Targets

Thought-provoking presentations by four keynote speakers. Dr. Corey Strickland, Merck, presents From Concept to Reality: Cryo-EM as an Integral Part of Drug Discovery and Development. Dr. Lionel Rougé, Genentech, shares his insights on Structural Characterization of Different TRPA1 Inhibitors. Dr. Kenneth Borelli. Schrödinger, speaks about Improving Protein-Ligand Modeling into Cryo-EM Data and the use of those Models in Drug Discovery Efforts. And Prof. Patrick Sexton, Monash University, explains the Use of Cryo-EM for GPCR Drug Discovery and Development.

Cryo-EM in Drug Discovery - Panel Discussion

Dr. Jeffrey Lengyel, Thermo Fisher Scientific, Dr. Benjamin Apker, Mitegen, Dr. Corey Strickland, Merck, and Dr. Denis Zeyer, Novalix, will elaborate their opinion on how cryo-EM technology accelerates drug design of intractable targets.

Ask the Experts | December 9, 2020

Enhanced automation for high throughput cryo-EM screening and data collection for drug design

Ask the Experts webinar highlighting recent advances in cryo-EM automation for increased productivity to provide structural insights for your drug discovery pipeline. Andreas Schenk, Novartis, and Ben Apker, MiTeGen, discuss how the state-of-the-art cryo-EM workflow automations compares to X-ray crystallography in terms throughput and resolution.

Cryo-EM in Drug Discovery Virtual Event | September 29, 2020

Latest scientific developments in cryo-electron microscopy and electron diffraction

Two keynote lectures from leaders in the field of cryo-EM and electron diffraction will present latest results and how these techniques enable them to push the boundaries of their pipeline and research projects.

Cryo-EM solution optimized for drug discovery

Learn more on our recently launched iSPA Workflow solution, specifically designed to accelerate the structure-based drug discovery process.

Round table discussion

Experts in the field will elaborate about their experiences with getting cryo-EM technology in-house and offer practical consideration for how to setup a successfully running cryo-EM workflow.

Samples


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.

Learn more ›


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.

Learn more ›


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.

Learn more ›


Techniques

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.

Learn more ›

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.

Learn more ›

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.

Learn more ›

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.

Learn more ›

Products

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Krios Rx Cryo-TEM

  • Industry leading productivity and ease of use
  • Fixed 300 kV voltage for SPA only
  • Pharma-dedicated service package for guaranteed reliability

Krios G4 Cryo-TEM

  • Improved ergonomics
  • Fits more easily into new and existing labs
  • Maximized productivity and automation
  • Best image quality for high-resolution 3D reconstruction

Glacios Cryo-TEM

  • Flexible Accelerating Voltage 80-200 kV
  • Industry-leading Autoloader for cryogenic sample manipulation
  • Small footprint
  • Enhanced ease-of-use

Tundra Cryo-TEM

  • Structural information at biologically relevant resolution
  • Space efficient and cost effective
  • Easy, iterative sample optimization
  • Unique AI algorithms for streamlined data collection

Vitrobot System

  • Fully automated sample vitrification
  • Blotting device
  • Semi-automated grid transfer
  • High sample throughput

Selectris and Selectris X Imaging Filters

  • Designed for high stability and atomic resolution imaging
  • Straightforward operation
  • Paired with the latest generation Thermo Scientific Falcon 4 Direct Electron Detector

EPU 2 Software

  • Microscope-embedded solution for single particle acquisition
  • Optimized for high-throughput particle collection
  • Compatible with film, CCD cameras, and direct electron detectors

Falcon 4i Detector

  • High throughput for more images per hour
  • Unsurpassed imaging quality with high DQE
  • Lossless data compression with EER

Ceta-D Camera

  • Optimum performance at any high tension (20–300 kV)
  • Compatible with post-column filters and spectrometers
  • Movie acquisition for dynamic studies

EM Services for Pharma

  • Maximize output with system uptime and throughput commitments
  • Drive improvement with enhanced visibility to system data
  • Comprehensive maintenance and applications support

EM Services for Single Particle Analysis

  • Empower your users so they can work with confidence
  • Keep step-by-step workflow guidance at your fingertips
  • Get set up for success with Workflow Validation

Contact us

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