Drug Discovery

Figure 1

Cryo-EM density map of a GPCR complex: glucagon-like

peptide-1 receptor (GLP1R) is an important target for

treatment of Type 2 diabetes. Most GLP1R agonists are injectable drugs and

therapeutic potential of this receptor is far from

exhausted. Using cryo-EM it

was possible to identify a new agonist pocket for non-

peptides. This result will help to find new oral medicines

that will be safer and better in protecting from Type 2

diabetes. Image based on PDB- entry 6ORV (released

08.01.2020) created with Pymol by Hans Raaijmakers

versatility of cryo-EM and to the variety of benefits made possible with this method. Based on the results of these applications, you can determine if the adoption of cryo-EM for your projects can lead to an increase in the number of valid results, there- by improving your rational design efforts. A substantial number of pharmaceutical compa-

nies have recently published papers providing proof of how cryo-EM delivered critical structural insights. In several cases, cryo-EM provided the insight that was unattainable with other methods, thus accelerating the path to drug discovery. In this article we describe the benefits of cryo-

EM in accelerating drug discovery and feature pharma use cases that recently have been pub- lished.

Applications of cryo-EM in Pharma Protein drug target classes A drug target is a molecule in the body, usually a protein, that is intrinsically associated with a par- ticular disease process and that could be addressed by a drug to produce a desired thera- peutic effect (from Comprehensive Medicinal Chemistry II, 2007). Common classes of drug tar- gets are proteins and nucleic acids. The definition can refer to the biological target of a pharmaco- logically-active drug compound, the receptor tar- get of a hormone (such as insulin), or some other target of an external stimulus. In this article we


present examples of how cryo-EM reveals the structure of biological drug targets which are most commonly proteins such as membrane pro- teins (GPCRs), ion channels, enzymes and hor- mone receptors. Cryo-EM was also crucial to reveal the structure of the virus binding sites and the influence of small molecules to a large protein drug target assemblies. GPCRs G protein-coupled receptors (GPCRs) are mem- brane proteins that regulate a variety of cellular responses to external stimuli. They are involved in a wide range of diseases and are a critical drug target; more than 50% of modern protein-based pharma is related to GPCRs. As membrane pro- teins, they are large, flexible and resistant to crys- tallisation, meaning traditional analytical tech- niques such as NMR and XRD cannot be used to characterise their structures. A collaborative pro- ject performed in conjunction with Dr Mazdak Radjainia, a staff scientist at Thermo Fisher Scientific, successfully employed cryo-EM to analyse the GPCR structure. In addition, researchers were able to capture the dynamic nature of these complexes, as structural families can be grouped and individually characterised using cryo-EM. Class B GPCRs are major targets for treatment of chronic disease, including dia- betes and obesity. Structures of active receptors revealed that peptide agonists engage deep within

Drug Discovery World Winter 2019/20

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