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Analytical & Structural Neuropharmacology

Celine Valant
David Thal
Arthur Christopoulos

Understanding the molecular basis and physiological consequences of allosteric modulation and biased agonism at G protein-coupled receptors

G protein-coupled receptors (GPCRs) represent the largest family of receptor proteins encoded by the human genome and the biggest class of current drug targets. These proteins can concomitantly interact with diverse endogenous and exogenous ligands and adopt multiple conformational states that couple to diverse signalling pathways. Our laboratory focuses on two key paradigms of drug action that arise as a consequence of these properties of GPCRs, specifically, allosteric modulation and biased agonism. These paradigms are revolutionizing modern drug discovery, and we investigate them using a multidisciplinary approach that encompasses structural and computational biology, molecular and mathematical modelling, medicinal chemistry, biochemistry and cellular signal transduction, native tissue bioassays and preclinical animal models. We are particularly interested in understanding how the phenomena of allosteric modulation and biased agonism can be applied to GPCRs implicated in neuropsychiatric disorders, such as schizophrenia, and neurodegenerative disorders, such as Alzheimer’s disease, but we also investigate GPCR targets implicated in other disease states. We apply a multi-disciplinary approach to interrogating GPCRs with a view to developing novel chemical probes and potential therapeutic leads.