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

GPCRs are important signal transduction proteins residing in the cell membrane and are essential regulators of many homeostatic processes and targeted by great than 30% of drugs. The beta-adrenoceptors (family A GPCRs), are key regulators of the cardiovascular and respiratory systems and well-established drug targets. beta1, beta2, and beta3 subtypes have distinct tissue distributions and pharmacological activity, but few known ligands show selectivity, making it difficult to research their distinct functions. We have recently identified, through advanced molecular modelling methods, a possible novel mode of binding of experimental subtype-selective ligands to 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 design, synthesise and pharmacologically characterise a library of ligands to test this hypothesis more rigorously. In parallel, molecular modelling studies will be performed that eventually will be correlated with pharmacological data.

Objectives:
-Design and synthesise a library of beta adrenoceptor ligands.
-Characterise these ligands pharmacologically, using cell-based assays.
-Use advanced molecular modelling methods, including flexible docking and molecular dynamics simulations, to predict the mode of binding of new beta adrenoceptor ligands to the proteins.
-Make calculations of the binding affinities, and identify structure-activity relationships.
Major methods:
-Synthetic organic chemistry and structural elucidation.
-Cell culture and pharmacological evaluation of ligand affinity and subtype selectivity.
-Molecular modelling of ligand-protein complexes and analysis of structure-activity data.