Molecular and in-silico interrogation of novel modes of binding at G protein-coupled receptors (GPCRs)

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GPCRs are important signal transduction proteins residing in the cell membrane and are essential regulators of many homeostatic processes and targeted by >30% of drugs. Research within the group has demonstrated that traditional computational approaches (based on models of published x-ray crystal structures) to rationalise how some ligands interact with their target receptor do not offer a valid explanation for experimentally observed activity, or are unable to sensibly accommodate these ligands in the accepted binding site. We have recently identified, through advanced molecular modelling methods, a possible novel mode of binding for ligands at the beta-adrenoceptors. This mode of binding may explain structure-activity relationship data that otherwise appears contradictory. An understanding of how these prototypical GPCRs interact with ligands is likely to be highly relevant to other members of the wider GPCR family. The aim of this multidisciplinary project will be to explore the potential for similar novel binding modes across other GPCR family members. Molecular modelling studies will be performed that will investigate these potential novel binding modes, and the results used to inform the synthesis of novel ligands produced to target these binding sites. The novel ligands will then be pharmacologically characterised. Building on our research with the beta-adrenoceptors, this chemical biology-focused project will span the disciplines of synthetic chemistry, pharmacology and computational chemistry to increase our understanding of the way ligands interact with members of the wider family of GPCRs.