Molecular Design and Pharmaceutical Biophysics, Institute of Pharmaceutical Sciences , Eberhard Karls University Tuebingen , Auf der Morgenstelle 8 , 72076 Tuebingen , Germany.
Center for Bioinformatics Tuebingen (ZBIT) , Eberhard Karls University Tuebingen , Sand 1 , 72076 Tuebingen , Germany.
J Chem Inf Model. 2019 Feb 25;59(2):885-894. doi: 10.1021/acs.jcim.8b00621. Epub 2019 Jan 28.
Halogen bonds have become increasingly popular interactions in molecular design and drug discovery. One of the key features is the strong dependence of the size and magnitude of the halogen's σ-hole on the chemical environment of the ligand. The term σ-hole refers to a region of lower electronic density opposite to a covalent bond, e.g., the C-X bond. It is typically (but not always) associated with a positive electrostatic potential in close proximity to the extension of the covalent bond. Herein, we use a variety of 30 nitrogen-bearing heterocycles, halogenated systematically by chlorine, bromine, or iodine, yielding 468 different ligands that are used to exemplify scaffold effects on halogen bonding strength. As a template interaction partner, we have chosen N-methylacetamide representing the ubiquitously present protein backbone. Adduct formation energies were obtained at a MP2/TZVPP level of theory. We used the local maximum of the electrostatic potential on the molecular surface in close proximity to the σ-hole, V , as a descriptor for the magnitude of the positive electrostatic potential characterizing the tuning of the σ-hole. Free optimization of the complexes gave reasonable correlations with V but was found to be of limited use because considerable numbers of chlorinated and brominated ligands lost their halogen bond or showed significant secondary interactions. Thus, starting from a close to optimal geometry of the halogen bond, we used distance scans to obtain the best adduct formation energy for each complex. This approach provided superior results for all complexes exhibiting correlations with R > 0.96 for each individual halogen. We evaluated the dependence of V from the molecular surface onto which the positive electrostatic potential is projected, altering the isodensity values from 0.001 au to 0.050 au. Interestingly, the best overall fit using a third-order polynomial function (R = 0.99, RMSE = 0.562 kJ/mol) with rather smooth transitions between all halogens was obtained for V calculated from an isodensity surface at 0.014 au.
卤键在分子设计和药物发现中已成为越来越受欢迎的相互作用。其关键特征之一是卤原子 σ-空穴的大小和强度强烈依赖于配体的化学环境。术语 σ-空穴是指相对于共价键，电子密度较低的区域，例如 C-X 键。它通常（但不总是）与紧邻共价键延伸处的正静电势相关联。在此，我们使用了各种系统卤化的 30 个含氮杂环，包括氯、溴和碘，得到了 468 种不同的配体，这些配体被用来举例说明骨架对卤键强度的影响。作为模板相互作用伙伴，我们选择了 N-甲基乙酰胺，代表普遍存在的蛋白质骨架。采用 MP2/TZVPP 理论水平计算加合物形成能。我们使用分子表面上紧邻 σ-空穴处静电势的局部最大值 V 作为描述符，来表示正静电势的大小，该正静电势表征了 σ-空穴的调谐。对配合物进行自由优化得到了与 V 相当好的相关性，但发现其用途有限，因为大量的氯化物和溴化物配体失去了卤键或表现出明显的次级相互作用。因此，从接近最优的卤键几何形状开始，我们使用距离扫描获得每个配合物的最佳加合物形成能。这种方法为所有表现出与每个卤素的 R > 0.96 相关的配合物提供了更好的结果。我们评估了将正静电势投影到分子表面上的 V 依赖性，改变了从 0.001 au 到 0.050 au 的等密度值。有趣的是，使用三阶多项式函数（R = 0.99，RMSE = 0.562 kJ/mol）获得了最佳整体拟合，并且所有卤素之间的过渡都相当平滑，这是通过在 0.014 au 的等密度表面上计算 V 获得的。
