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Collaborative Network To Define The Molecular Determinants Of G Protein Coupled Receptor Clinical Efficacy

Funder Wellcome Charity-funded
Recipient organisation University of Glasgow
Funding £4.2M
Period Jan 2017 — Jan 2022

In plain English

AI plain-English summary

About a third of all prescription drugs work by latching onto a family of proteins on cell surfaces called G protein-coupled receptors (GPCRs), yet drug developers are increasingly failing to predict which of these compounds will actually work in patients. The problem is a fundamental gap in knowledge. Scientists know that GPCRs trigger a cascade of signals inside cells, but they do not fully understand the molecular “rules” that govern how a drug’s initial binding to a receptor leads to a specific clinical outcome—or why that outcome can change in disease. This project will use two high-value targets for neurodegenerative disease and schizophrenia—the M1 and M4 muscarinic acetylcholine receptors—to map those rules across three stages: the trigger (drug–receptor interaction), the response (signalling in cells and tissues), and the outcome (physiological effect in animal models). If successful, the research will produce a predictive framework for designing GPCR drugs with greater on-target efficacy and fewer side effects. This is fundamental science with a clear translational goal: to replace the current trial-and-error approach to GPCR drug development with rational design, potentially accelerating the pipeline for safer treatments for conditions such as Alzheimer’s disease and schizophrenia.

View original technical description
Despite the fact that ~30% of marketed drugs target G protein-coupled receptors (GPCRs), the attrition rate of GPCR drug discovery programmes is increasing. This failure rate is rooted in our lack of fundamental understanding of novel paradigms of GPCR activation and signalling and how they are modified by disease. Using exemplar GPCR targets of high therapeutic value for neurodegenerative disease and schizophrenia (M1/M4 muscarinic acetylcholine receptors), we will address this knowledge gap by determining the molecular and cellular “rules” that underlie the three key stages of GPCR functionality (Trigger-Response-Outcome). By defining these rules we aim to predict the clinical efficacy of candidate GPCR-drugs. Specifically, we will: • Correlate atomic level investigation of ligand-GPCR interaction and signaling with physiological responses in target cells/tissues. • Establish the physiological/clinical outcome of defined ligand-GPCR pairings in animal models of disease. • Translate the understanding (rules) of how ligand-GPCR interaction relates to physiological/clinical outcomes, to the design of novel GPCR ligands. Through an extensive collaborative network of world leading GPCR scientists including clinical and industrial collaborators this programme will establish the molecular rules and pharmacological principles that will allow for the rational design of clinically effective GPCR-drugs with greater on-target efficacy and reduced adverse effects.

View the original record at the funder ↗

Researchers

Andrew Tobin (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Molecular and in-silico interrogation of novel modes of binding at G protein-coupled receptors (GPCRs)
Predictive modelling of GPCR druggable allosteric sites
A dynamic view of GPCR-G protein complexes: insight into partial agonism and G protein selectivity
Developing a molecular model of GPCR basal activity and inverse agonism
Development of a novel fragment screening platform for G protein-Coupled Receptors

Original classification

Collaborative Award in Science

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