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. With 13 out of the top 50 prescription drugs sold in the USA in 2010 being GPCR targeting drugs, this makes 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 remains untargeted by drugs, even though many are strongly associated with disease. This reflects the difficulty of identifying and optimising drugs that act at GPCRs.

Most GPCRs are activated through the interaction, or binding, of natural ligands such as hormones or neurotransmitters (e.g. adrenaline, dopamine, oxytocin) to the GPCR’s ligand binding site. 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 the ligand’s binding or ‘docking’ site 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 of its natural ligand. However, one of the main reasons for drug side effects is that these drugs may also bind to similar sites on other receptor family members (off-targets), causing unwanted physiological responses. Thus we need new ways to identify and design more selective GPCR-targeting drugs to treat many diseases.