Department of Chemistry, Universitat de les Illes Balears, Crta. de Valldemossa km 7.5, 07122, Palma (Baleares), Spain.
van 't Hoff Institute for Molecular Sciences, Universiteit van Amsterdam, Science Park 904, 1098, XH, Amsterdam, The Netherlands.
Chemistry. 2019 Oct 17;25(58):13436-13443. doi: 10.1002/chem.201903404. Epub 2019 Sep 17.
Studying noncanonical intermolecular interactions between a ligand and a protein constitutes an emerging research field. Identifying synthetically accessible molecular fragments that can engage in intermolecular interactions is a key objective in this area. Here, it is shown that so-called "π-hole interactions" are present between the nitro moiety in nitro aromatic ligands and lone pairs within protein structures (water and protein carbonyls and sulfurs). Ample structural evidence was found in a PDB analysis and computations reveal interaction energies of about -5 kcal mol for ligand-protein π-hole interactions. Several examples are highlighted for which a π-hole interaction is implicated in the superior binding affinity or inhibition of a nitro aromatic ligand versus a similar non-nitro analogue. The discovery that π-hole interactions with nitro aromatics are significant within protein structures parallels the finding that halogen bonds are biologically relevant. This has implications for the interpretation of ligand-protein complexation phenomena, for example, involving the more than 50 approved drugs that contain a nitro aromatic moiety.
研究配体与蛋白质之间的非经典分子间相互作用是一个新兴的研究领域。确定可以发生分子间相互作用的可合成的分子片段是该领域的一个关键目标。本文表明，在硝基芳族配体中的硝基部分和蛋白质结构中的孤对之间存在所谓的“π-hole 相互作用”（水和蛋白质羰基和硫）。在 PDB 分析中发现了大量结构证据，计算表明配体-蛋白质π-hole 相互作用的相互作用能约为-5 kcal/mol。突出显示了几个例子，其中π-hole 相互作用导致硝基芳族配体与类似的非硝基类似物相比具有更高的结合亲和力或抑制作用。在蛋白质结构中发现π-hole 相互作用与硝基芳烃显著相关，这与卤键具有生物学相关性的发现是一致的。这对配体-蛋白质络合现象的解释有影响，例如涉及 50 多种含有硝基芳族部分的已批准药物。
