Dynamic pharmacophores unveil binding mode ensembles for classical partial agonists at the M2 receptor

For the prototypic M 2 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 pharmacophores to unveil binding mode ensembles for classical M 2 partial agonists. We report correlations between the spatial distribution of lipophilic contacts and ligand efficacy and demonstrate the applicability of dynamic pharmacophores to analyze subtle binding mode changes.