CHISHIKI

Drug Discovery

Drug Discovery Using Stabilised GPCR Technology

By Eugenia Sergeev | Nov 20, 2019

About the Conference

What A Chemist Needs To Know About Biology 1: In Vitro Biology

Organised by SCI’s Young Chemists’ Panel

11 November 2019

London, UK

Conference Website

 

Summary          

Eugenia Sergeev, Research Scientist, Molecular Pharmacology, attended the educational conference named “What A Chemist Needs To Know About Biology 1: In Vitro Biology” organised by SCI’s Young Chemists’ Panel within the Society of Chemical Industry in London, UK on 11th November and delivered a lecture on “Drug Discovery Using Stabilised GPCR Technology”.

 

Abstract

G protein-coupled receptors (GPCRs) are a well-established family of drug targets that are implicated in a wide range of diseases and represent >30% of all drugs approved by the FDA. Despite these successes, a large proportion of this receptor family remain untargeted by therapeutics and thus offer significant opportunities in drug discovery. Sosei Heptares uses its proprietary StaR® technology to thermostabilise GPCRs by mutagenesis into a chosen conformational state. These purified proteins can then be used for biophysical screening techniques and crystallisation to yield X-ray structures that facilitate hit identification and structure-based drug design. Such an approach is particularly suitable for more challenging drug targets as it enables e.g. rational compound design to achieve subtype selectivity and screening for ligands binding specifically to the desired conformational state of the receptor. By utilising this StaR® technology, Sosei Heptares has solved structures of many GPCRs and established a broad drug discovery pipeline spanning a range of therapeutic areas including neurology, gastrointestinal disorders and oncology. This talk will use the discovery of HTL0014242 (a negative allosteric modulator of the metabotropic glutamate receptor 5) as a case study to demonstrate how StaR® technology can support the drug discovery process. Furthermore, the importance of thorough target validation of less well understood receptor drug targets, such as orphan GPCRs with no known endogenous ligand, will be discussed.

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