Laboratorium für Organische Chemie, ETH Zürich, Hönggerberg, HCI, 8093 Zürich, Switzerland.
ChemMedChem. 2013 Mar;8(3):397-404. doi: 10.1002/cmdc.201200512. Epub 2013 Jan 25.
The less polar π-surface of protein amide groups is exposed in many receptor binding sites, either as part of the backbone or in Gln/Asn side chains. Using quantum chemical calculations and Protein Data Bank (PDB) searches on model systems, we investigate the energetics and geometric preferences for the stacking on amide groups of a large number of heteroarenes that are relevant to medicinal chemistry. From this study, we discern that the stacking energy of an aromatic ligand substituent can be improved by: 1) orienting the fragment dipole vector such that it is aligned in an antiparallel fashion with the dipole of the interacting protein amide group, 2) increasing its dipole moment, and 3) decreasing its π-electron density. These guidelines should be helpful to more rationally exploit this interaction type in future structure-based drug design.
许多受体结合位点中，蛋白质酰胺基团的非极性π-面暴露在外，或者作为骨架的一部分，或者在 Gln/Asn 侧链中。本研究使用量子化学计算和针对模型系统的蛋白质数据库（PDB）搜索，研究了大量与药物化学相关的杂芳烃在酰胺基团上堆积的能量学和几何偏好。通过这项研究，我们发现芳基配体取代基的堆积能可以通过以下方式得到改善：1）使片段偶极子矢量定向，使其与相互作用的蛋白质酰胺基团的偶极子呈反平行排列，2）增加其偶极矩，3）降低其π-电子密度。这些准则应该有助于在未来基于结构的药物设计中更合理地利用这种相互作用类型。
