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

Wunsch, F.; Kauk, M.; Filor, J.; Wolber, G.; Holzgrabe, U.; Hoffmann, C.; Bermudez, M.

doi:10.1101/2025.09.17.671681

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bioRxiv · 10.1101/2025.09.17.671681

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

Wunsch, F.·Kauk, M.·Filor, J.·Wolber, G.·Holzgrabe, U.·Hoffmann, C.·Bermudez, M.

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Abstract

For the prototypic 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 pharmacophores 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 pharmacophores to analyze subtle binding mode changes.

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Wunsch, F., Kauk, M., Filor, J., Wolber, G., Holzgrabe, U., Hoffmann, C., Bermudez, M.. 2025-09-18. Dynamic pharmacophores unveil binding mode ensembles for classical partial agonists at the M2 receptor. https://doi.org/10.1101/2025.09.17.671681

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