Dynamic pharmacophores unveil binding mode ensembles for classical partial agonists at the M_2_ receptor

Abstract

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.