Stacking Interactions of Heterocyclic Drug Fragments with Protein Amide Backbones
Stacking Interactions of Heterocyclic Drug Fragments with Protein Amide Backbones
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DOI：
10.1002/cmdc.201700721
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发表时间：
2018-04-23
期刊：
影响因子：
3.4
通讯作者：
Wheeler, Steven E.
中科院分区：
文献类型：
--
作者：
Bootsma, Andrea N.;Wheeler, Steven E.
堆积相互作用可能是药物结合的重要热函贡献者。芳烃和酰胺基团面之间发生的堆积相互作用是研究较少的。鉴于药物中杂环的普遍存在，再加上蛋白质主链中丰富的酰胺，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。 (ChemMedChem2013, 8, 397-404) 研究了具有一组 18 个杂环的模型酰胺的堆叠二聚体，表明计算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。我们通过使用更稳健的从头计算方法，考虑了相同模型酰胺的堆叠二聚体与药物中常见的 28 个杂环的更大集合。虽然这些新数据的总体趋势证实了 Diederich 等人的许多结果，但这些数据提供了关于酰胺堆积相互作用性质的更精确的观点。我们提出了基于分子偶极矩和芳烃上方电场强度的酰胺堆积相互作用能的稳健评分函数。
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 -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 etal. (ChemMedChem2013, 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 abinitio methods. While the overall trends in these new data corroborate many of the results of Diederich etal., 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.