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Dynamics-based assessment of subtle changes in GPCR ligand recognition and function

Affiliation
University of Münster, Institute for Pharmaceutical and Medicinal Chemistry, Münster, Germany
Wunsch, Friederike;
Affiliation
Freie Universität Berlin, Institute of Pharmacy, Berlin, Germany
Puls, Kristina;
Affiliation
Freie Universität Berlin, Institute of Pharmacy, Berlin, Germany
Wolber, Gerhard;
Affiliation
University of Münster, Institute for Pharmaceutical and Medicinal Chemistry, Münster, Germany
Bermudez, Marcel

G protein-coupled receptors (GPCRs) regulate a myriad of physiological processes in the human body, but their complex mechanisms still need to be fully understood. To analyze the dynamic behavior of GPCR-ligand complexes, we use a fully automated combination of MD simulations and 3D pharmacophores (dynophores), which enables the analysis of receptor-ligand interactions throughout a MD simulation in a spatiotemporal manner. Here, we present three applications of the dynophore approach, in which subtle differences in ligand recognition and resulting functional effects could be unveiled.
In our first application, we focused on subtype-specific binding site characteristics of the sphingosine-1-phosphate receptor family. We analyzed differences in binding mode dynamics to rationally explain the selectivity profile of marketed drugs including Siponimod, and Ozanimod. In a second application, we provide mechanistic insight into peptide binding to the atypical chemokine receptor 3 (ACKR3). The reported opioid scavenging function renders ACKR3 a potential analgesic target without typical opioid-related side effects. The third application focuses on the possibility of binding mode ensembles as a potential mechanism for partial receptor activation of muscarinic receptors. The dynamic interaction patterns can be correlated with the agonistic efficiency, contributing to the mechanistic understanding of partial agonism.
The diversity of the three applications concerning receptor family, ligand type, and studied function demonstrates the broad applicability of the dynophore approach to elucidate complex mechanisms in GPCR functionality.

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