Stacking interactions can be important enthalpic contributors to drug binding. Among the less well‐studied stacking interactions are those occurring between an arene and the π‐face of an amide group. Given the ubiquity of heterocycles in drugs, combined with the abundance of amides in the protein backbone, optimizing these noncovalent interactions can provide a potential route to enhanced drug binding. Previously, Diederich et al. (ChemMedChem 2013, 8, 397–404) studied stacked dimers of a model amide with a set of 18 heterocycles, showing that computed interaction energies correlate with the dipole moments of the heterocycles and providing guidelines for the optimization of these interactions. We considered stacked dimers of the same model amide with a larger set of 28 heterocycles common in pharmaceuticals, by using more robust ab initio methods. While the overall trends in these new data corroborate many of the results of Diederich et al., these data provide a more refined view of the nature of amide stacking interactions. We present a robust scoring function for amide stacking interaction energies based on the molecular dipole moment and strength of the electric field above the arene.

中文翻译：

---

杂环药物片段与蛋白质酰胺骨架的堆积相互作用

堆积相互作用可能是药物结合的重要焓贡献者。在研究较少的堆叠相互作用中，是芳烃和酰胺基团的π面之间发生的相互作用。考虑到药物中杂环的普遍存在，再加上蛋白质骨架中酰胺的大量存在，优化这些非共价相互作用可以提供增强药物结合的潜在途径。此前，Diederich等人。（ChemMedChem 2013，8（397–404）研究了具有一组18个杂环的酰胺模型的堆叠二聚体，表明计算出的相互作用能与杂环的偶极矩相关，并为优化这些相互作用提供了指导。通过使用更可靠的从头算方法，我们考虑了相同模型酰胺的堆叠二聚体，在医药中具有较大的28个杂环。尽管这些新数据的总体趋势证实了Diederich等人的许多结果，但这些数据提供了有关酰胺堆积相互作用性质的更精确视图。我们基于分子偶极矩和芳烃上方电场的强度，为酰胺堆积相互作用能提供了强大的评分功能。