GPCRs

Greater structural insight of GPCRs is enabling drug discovery programmes

G protein-coupled receptors (GPCRs) are hugely important membrane protein drug targets, being involved in virtually all physiological processes and implicated in all major disease areas.

As a consequence, GPCRs are targeted by 25–30% of marketed drugs (two examples are shown below).¹ Despite the long history of GPCR research, they continue to be actively pursued in drug discovery: firstly, because there is still great potential to develop new and improved medicines for well-established targets – for example, with better receptor specificity and therefore a reduced side-effect profile; and secondly in order to find medicines that act on presently non-drugged, disease-relevant receptors.

GPCRs molecular structures Loratadine and Losartan

GPCR Purification and Structure Determination

Domainex believes that the key to unlocking modern GPCR research is gaining ready access to purified soluble receptors for assays and structural biology. To this end it is playing a leading role in developing a cutting-edge GPCR purification system by using our detergent-free PoLiPa technology. We have established a rapid and generic platform for preparation of purified GPCR reagents to enable biophysical techniques, structural biology, and ‘panning’ approaches to the screening of antibodies and very large (e.g. DNA-encoded) chemical libraries. This capability fits well with our in-house expertise in structure determination of GPCRs by X-ray and Cryo-EM methods. Emerging trends in GPCR drug discovery show that there are growing opportunities for success in areas that move away from conventional strategies against well-established targets², and we believe that our exciting PoLiPa and structural biology platform will be invaluable in exploiting this huge potential.

GPCR Assay Development

In a more tried-and-tested vein, cellular functional readouts are an invaluable tool for developing GPCR medicines. Domainex cell biologists are well-equipped to develop assays across a broad range of second messenger (e.g. cAMP, inositol phosphate, calcium and β-arrestin) and downstream signalling cascades (e.g. phospho-proteins and phenotypic readouts). We are also highly experienced in generating stable cell lines to support these assays. For example, we have developed a FLIPR calcium assay against the human neurotensin 1 receptor (NTR1) that we expressed in a CHO stable cell line. This was used to corroborate agonist and antagonist pharmacology of known tool ligands. Click here for the full case study.

Domainex medicinal and computational chemists have a vast amount of experience in GPCR drug design and can support client projects at all stages of preclinical development. If you would like to access our expertise to support your own programme we would be delighted to hear from you.

References

1. GPCRs as targets for approved drugs: How many targets and how many drugs? Sriram, K. & Insel, P. A. Mol. Pharmacol. 2018, 93 (4) 251-258. doi:10.1124/mol.117.111062

2. Trends in GPCR drug discovery: New agents, targets and indications. Hauser, A. S., Attwood, M. M., Rask-Andersen, M., Schiöth, H. B. & Gloriam, D. E. Nat. Rev. Drug Discov. 2017, 16, 829–842.