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.针对典型M2受体，此前已有研究证实双位点部分激动剂（dualsteric partial agonists）可同时稳定该受体的激活态与失活态，但正构位点部分激动剂（orthosteric partial agonists）是否具备类似的作用机制仍不明确。本研究采用动态药效团模型（dynamic pharmacophore models），对经典M2受体部分激动剂的结合模式集合进行解析。我们揭示了亲脂性接触的空间分布与配体效能之间的相关性，并证实了动态药效团模型可用于分析细微的结合模式变化。受体层面的部分激动作用可在降低不良反应的同时，产生临床期望的治疗效果。因此，阐明其潜在的结构机制对于定制化药物研发至关重要。