Thermo Scientific workflow aims to accelerate drug development
According to the company, the Thermo Scientific iSPA Workflow is the first commercially available, single-particle analysis workflow solution. With pharmaceutical labls and partners increasingly use cryo-electron microscopy to discover the structures of hard-to-crystalize molecules at near-atomic resolution, they also are seeking ways to increase productivity, so that they can move more quickly from early drug discovery to clinical trials.
Outsourcing-Pharma (OSP) recently spoke with Raymond Schrijver (RS), senior director of pharma at Thermo Fisher, about the importance of speeding drug discovery and development, conserving costs where possible, and how laboratory technology can help meet such pressing challenges.
OSP: Could you please talk about some of the key obstacles in drug discovery, and how these challenges might have changed/evolved in recent years?
RS: One of the key challenges in drug discovery is accurate prediction for properties of new molecules. To arrive at a drug candidate thousands of compounds have to be synthesized over several years and still a significant portion of drug discovery projects fails due to poor properties of drugs.
Structure-based drug discovery methods can reduce the time, cost and as well as failure rates of this process and are now generally preferred wherever structure is feasible. Protein crystallography has been highly successful in structure enablement of soluble drug target classes such as kinases and proteases but has as primary requirement that these proteins need to form crystals.
Despite intensive efforts, many protein families including membrane proteins and large soluble assemblies have remained recalcitrant to crystallization. As an example, though membrane proteins account for over 60% of drug targets, only 2% of existing crystal structures represent membrane proteins, which means the structural information for many of such targets of interest to pharma remain unknown.
OSP: What solutions (if any) have drug discovery/development professionals pursued to try and alleviate these challenges?
RS: Until now, In the absence of structural information, homology modeling of the target’s structure is used to provide structural insights on the condition that at least one homologous structure of the protein exists at the Protein Data Bank.
Cryo-EM Single Particle Analysis (SPA) allows the direct visualization of not just large macromolecule but also smaller protein complexes, including membrane proteins such as GPCRs and is the method of choice to address these intractable targets. With cryo-EM, it is now commonplace to generate structures at a resolution that can enable the identification of small molecules and ions.
The highest cryo-EM resolution structures are now in the near-atomic to atomic range which makes it easier to unambiguously assign the binding mode of these molecules. The so-called resolution revolution of cryo-EM has now allowed this methodology to be a very useful tool in SBDD.
OSP: Which of these types of solutions work better than others?
RS: Importantly, structures determined by X-ray crystallography very often represent just one snapshot of one specific conformation of the target protein, which may not necessarily represent the most common conformation of that target. Cryo-EM SPA on the other hand, allows the structural determination of protein targets in their near-native states.
As pharmaceutical labs are now turning to cryo-EM to uncover the structures of difficult-to-crystalize molecules at near atomic resolution, there are still bottlenecks such as the technology being perceived as too difficult to operate. Currently, a new user may require several weeks to months of training before they become independent.
Another bottleneck is the low structure throughput to generate that first structure followed by several repeat structures of the target in combination with drug compounds. And importantly, the reliability of the instruments to minimize risks of downtime and troubleshooting, which can reduce the full utilization of the instrument.
OSP: Could you please describe the iSPA Workflow in a nutshell, and what sets this particular technology apart from other, similar solutions currently in use?
RS: The iSPA Workflow is the first complete SPA-dedicated solution specifically designed for Pharma to solve this problem by providing an easy-to-use, highly productive and automation-enhanced solution to match the pace of drug discovery. Developed with input from users in the pharmaceutical industry, the workflow is designed to support structural biologists of all experience levels from sample vitrification to data collection to deliver faster results, higher resolution and reduce the cost of bringing new drugs to the market.
Krios Rx high-end cryo-TEM flagship of the iSPA workflow – is a SPA-only microscope dedicated for pharma drug discovery process. Krios Rx comes with a powerful combination of innovative features and enhanced automation for unattended data collection to provide the optimal throughput with a guaranteed productivity; this is ideal for generating de novo and repeat structures in combination with their drug compounds quickly to match the timeline for lead discovery and optimization.
When we combine all this on a real sample, we can now get the structure of apoferritin to near-atomic resolution within 10 minutes of data collection. On a human membrane protein such as the GABA A receptor, we can get a structure of this receptor bound to its drug compound n 3-4 hours to near-atomic resolution; this will cryo-EM solution will certainly change the pace of drug discovery.
