A dynamic view on receptor-ligand interactions

Teilnahme an der Veranstaltung per Zoom (Meeting ID: 621 2506 6616, Passcode: DPhG) oder in Präsenz im großen Hörsaal der Pharmazeutischen Institute, Corrensstraße 48 in Münster

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Ligands for G protein-coupled receptors (GPCRs) represent the largest class of marketed dugs and are essential therapeutics for a plethora of clinical indications. Surprisingly, almost all of them have been developed under the assumption that GPCRs are simple on-off switches. Over the last decade specific receptor-ligand complexes were determined by crystallography or cryo-EM providing an indispensable structural view on this protein class. However, the resulting atomic models represent single static and energetically favoured conformations of highly flexible receptors. For a mechanistic understanding of ligand-dependent receptor functionality we need to consider GPCR-ligand complexes as dynamic entities. Here, we report use cases of a fully-automated approach to combine three-dimensional pharmacophore models with molecular dynamics (MD) simulations: dynophores. This technique allows us to trace receptor-ligand interactions in space and time throughout the MD trajectory and provides a perfect tool for the communication with pharmacologists and chemists. Subtle changes in binding modes and interaction frequencies can be analysed and quantitatively compared providing away to rationally explain how ligand binding to a receptor triggers a distinct pharmacological effect. We will showcase how the application of dynophores helped us to mechanistically understand complex pharmacological functionalities including subtype selectivity, partial agonism and biased signalling.