Dynamic Pharmacophores Unveil Binding Mode Ensembles for Classical Partial Agonists at the M2 Receptor

For the prototypical M₂ receptor, it has been previously demonstrated that dualsteric partial agonists can stabilize both active and inactive receptor states, but it remains unclear whether orthosteric partial agonists have a similar mechanism. Here, we apply dynamic pharmacophore models to unveil binding mode ensembles for classical M₂ partial agonists. We report correlations between the spatial distribution of lipophilic contacts and ligand efficacy and demonstrate the applicability of dynamic pharmacophore models to analyze subtle binding mode changes. Partial agonism at the receptor level can translate into clinically desired effects while reducing adverse side effects. Thus, an understanding of the underlying structural mechanism is essential for tailored drug design.