|Most GPCR ligands activate multiple signalling pathways spanning four G protein classes: Gq/11, Gi/o, Gs and G12/13 with 16 subtypes. Furthermore, arrestin proteins mediate GPCR signalling, desensitisation and internalisation.||A biased ligand preferentially actives only one singalling pathway. A new candidate analgesic drug, oliceridine selectively stimulates the μ-opioid receptor Gi/o pathway, but lacks the ß-arrestin mediated constipation and respiratory depression.|
Drug development has an 86% failure rate –mainly due to insufficient efficacy or to side effects. For GPCRs this could be solved by ‘biased ligands’ which re-route cellular pathways to therapeutic actions away from side effects. However, this huge potential is inaccessible because few GPCRs have biased ligands and we do not yet know the molecular mechanisms to rationally design them.
Biased ligands: We will create a database of known biased ligands and identify new such ligands through computational drug design. A PhD training network, SAFER has set out to identify biased ligands for the serotonin 2A receptor (5-HT2A), which mediates the effect of recreational drugs, e.g. LSD and agents in clinical trials for treatment-resistant depression and anxiety. A Novo Nordisk Foundation Ascending Investigator grant focuses on the free fatty acid receptor 4 – a target for diabetes and inflammation – will also pharmacologically profile the signalling of known reference ligands and drugs to identify signalling bias. Going forward, we would like to take on a wider challenge to build a virtual screening pipeline to identify novel ligands with signalling bias for many more GPCRs.
Pathway effects: We will make an online atlas of the physiological and therapeutic effects of individual GPCR signalling pathways, thereby providing the rationale for which pathways to target in drug discovery and receptor function studies. So far, few such effects are known. However, much more such data will soon become available, from e.g. the new European research network on signal transduction, ‘ERNEST’ and as more clinical trials evaluate biased candidate drugs. We are also exploring computational drug design to identify G protein/b-arrestin inhibitors that would constitute very valuable tools to map (patho)physiological pathways.
Structures and mechanisms: We plan to (application pending) to develop protein engineering and online tools to ease the generation of GPCR structures bound to G proteins and biased ligands, which could elucidate molecular mechanisms to design biased tool compounds and drugs.