Enabling technologies for structure based drug design at G protein coupled receptors

G protein-coupled receptors (GPCRs) are a large family of proteins (>800 gene members) located on the surface of all cells in the body, particularly in the brain.

These proteins sense stimuli such as light, smells, hormones and neurotransmitters, and initiate cellular responses to these cues. GPCR signalling controls virtually every physiological process in the body, making these receptors the targets of many current drugs treating conditions like pain, hypertension, schizophrenia and asthma. 13 out of the top 50 prescription drugs sold in the USA in 2010 were GPCR targeting drugs, making these the largest class of drug targets; in fact, they accounted for more than $US28 billions of sales that year in the USA alone. While this seems impressive, up to 80% of this receptor family remain untargeted by drugs, even though many are strongly associated with disease. This reflects the difficulty associated with identifying and optimizing drugs that act at GPCRs.

Most GPCRs are activated though the interaction, or binding, of natural ligands such as hormones or neurotransmitters (e.g. adrenaline, dopamine, oxytocin) to the GPCR’s ligand binding site (Figure 1). A major challenge in GPCR drug discovery is achieving receptor selectivity. The GPCR gene super-family is made up of numerous sub-families that are activated by the same ligand, but may control different physiological processes. This means that the binding or “docking” site (Figure 1) of the ligand is very similar in these family members. Typically in drug discovery we search for synthetic compounds that can also bind to this receptor site, to change the signalling of the receptor, independent to its natural ligand. One of the main reasons for drug side effects however, is that these drugs may also bind to similar sites on other receptor family members (off targets), causing physiological response that are unwanted. Thus we need new ways to identify and design more selective GPCR targeting drugs to treat many diseases.


Structure-based drug design

To achieve receptor selectivity, we need to understand how natural ligands, and drug candidates, bind to receptors at the atomic level (Figure 1). This then allows the design of new drugs with optimized interactions for a specific receptor, making the drug more selective. This process is called structure-based drug design.

To probe the atomic-level structures of GPCRs, we need to be able to purify these receptors from cells. A huge challenge has been that most GPCRs are very unstable and “fall apart” during purification, or during the experiments needed to perform “structure-based drug design”. We work on developing new technologies to get around this problem, such as Cellular High-throughput Encapsulation Solubilization and Screening, or CHESS, which allows us to engineer very stable receptors for drug discovery. The CHESS technology was spun out into a biotechnology company called G7 Therapeutics in 2013. Stabilised GPCRs can be produced in cells such as bacteria, purified and stored in the freezer until needed. This technology has some limitations however, and we are constantly working on developing new methods to further our understanding of the structure of many different GPCRs with the ultimate goal of designing better drugs.

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