BioISI - Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, C8 bdg, 1749-016 Lisboa, Portugal.
Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal.
J Am Chem Soc. 2021 Mar 24;143(11):4253-4267. doi: 10.1021/jacs.0c12470. Epub 2021 Mar 9.
Halogen bonds (XBs) are noncovalent interactions where halogen atoms act as electrophilic species interacting with Lewis bases. These interactions are relevant in biochemical systems being increasingly explored in drug discovery, mainly to modulate protein-ligand interactions, but are also found in engineered protein or nucleic acid systems. In this work, we report direct evidence for the existence of XBs in the context of biological membrane systems, thus expanding the scope of application of these interactions. Indeed, our molecular dynamics simulations show the presence of favorable interactions between halobenzene derivatives and both phosphate or ester oxygen acceptors from a model phospholipid bilayer, thus supporting the existence of XB-mediated phospholipid-halogen recognition phenomena influencing the membrane insertion profile of the ligands and their orientational preferences. This represents a relevant interaction, previously overlooked, eventually determining the pharmacological or toxicological activity of halogenated compounds and hence with potential implications in drug discovery and development, a place where such species account for a significant part of the chemical space. We also provide insights into a potential role for XBs in the water-to-membrane insertion of halogenated ligands as XBs are systematically observed during this process. Therefore, our data strongly suggest that, as the ubiquitous hydrogen bond, XBs should be accounted for in the development of membrane partition models.
卤素键（XBs）是非共价相互作用，其中卤素原子作为亲电物种与路易斯碱相互作用。这些相互作用在生化系统中具有重要意义，正在药物发现中得到越来越多的探索，主要用于调节蛋白质-配体相互作用，但也存在于工程化的蛋白质或核酸系统中。在这项工作中，我们报告了生物膜系统中存在 XB 的直接证据，从而扩展了这些相互作用的应用范围。事实上，我们的分子动力学模拟表明，卤代苯衍生物与模型磷脂双层中的磷酸或酯氧受体之间存在有利的相互作用，从而支持 XB 介导的磷脂-卤素识别现象的存在，这种现象影响配体的膜插入特性及其取向偏好。这是一种以前被忽视的相关相互作用，最终决定了卤代化合物的药理学或毒理学活性，因此在药物发现和开发中具有潜在意义，在这些领域中，这些物质占据了很大一部分化学空间。我们还提供了关于 XB 在卤代配体从水到膜插入过程中的潜在作用的见解，因为在这个过程中系统地观察到了 XB。因此，我们的数据强烈表明，就像普遍存在的氢键一样，在开发膜分配模型时应该考虑 XB。
