Key Laboratory of Nuclear Medicine, Ministry of Health, & Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine , Wuxi 214063, P. R. China.
Department of Anesthesia, Stanford University School of Medicine , 300 Pasteur Drive, Stanford, California 94305, United States.
J Phys Chem B. 2017 Jun 22;121(24):5883-5896. doi: 10.1021/acs.jpcb.7b02079. Epub 2017 Jun 8.
Propofol (PFL, 1-hydroxyl-2,6-diisopropylbenzene) is currently used widely as one of the most well-known intravenous anesthetics to relieve surgical suffering, but its mechanism of action is not yet clear. Previous experimental studies have demonstrated that the hydroxyl group of PFL plays a dominant role in the molecular recognition of PFL with receptors that lead to hypnosis. To further explore the mechanism of anesthesia induced by PFL in the present work, the exact binding features and interaction details of PFL with three important proteins, human serum albumin (HSA), the pH-gated ion channel from Gloeobacter violaceus (GLIC), and horse spleen apoferritin (HSAF), were investigated systematically by using a rigorous three-layer ONIOM (M06-2X/6-31+G*:PM6:AMBER) method. Additionally, to further characterize the possible importance of such hydroxyl interactions, a similar set of calculations was carried out on the anesthetically inactive fropofol (FFL, 1-fluoro-2,6-diisopropylbenzene) in which the fluorine was substituted for the hydroxyl. According to the ONIOM calculations, atoms in molecules (AIM) analyses, and electrostatic potential (ESP) analyses, the significance of hydrogen bond, halogen bond, and hydrophobic interactions in promoting proper molecular recognition was revealed. The binding interaction energies of PFL with different proteins were generally larger than FFL and are a significant determinant of their differential anesthetic efficacies. Interestingly, although the hydrogen-bonding effect of the hydroxyl moiety was prominent in propofol, the substitution of the 1-hydroxyl by a fluorine atom did not prevent FFL from binding to the protein via a halogen-bonding interaction. It therefore became clear that multiple specific interactions rather than just hydrogen or halogen bonds must be taken into account to explain the different anesthesia endpoints caused by PFL and FFL. The contributions of key residues in ligand-receptor binding were also quantified, and the calculated results agreed with many available experimental observations. This work will provide complementary insights into the molecular mechanisms of anesthetic action for PFL from a robust theoretical point of view. This will not only assist in interpreting experimental observations but will also help to develop working hypotheses for further experiments and future drug design.
丙泊酚（PFL，1-羟基-2,6-二异丙基苯）目前广泛用作最著名的静脉麻醉剂之一，用于缓解手术痛苦，但它的作用机制尚不清楚。先前的实验研究表明，PFL 的羟基在 PFL 与导致催眠的受体的分子识别中起主导作用。为了进一步探索 PFL 麻醉诱导的机制，本工作系统地研究了 PFL 与三种重要蛋白质（人血清白蛋白（HSA）、来自 Gloeobacter violaceus 的 pH 门控离子通道（GLIC）和马脾脱铁铁蛋白（HSAF））的确切结合特征和相互作用细节，使用严格的三层 ONIOM（M06-2X/6-31+G*:PM6:AMBER）方法。此外，为了进一步表征这种羟基相互作用的可能重要性，对麻醉活性较低的氟丙泊酚（FFL，1-氟-2,6-二异丙基苯）进行了类似的计算，其中羟基被氟取代。根据 ONIOM 计算、原子在分子（AIM）分析和静电势（ESP）分析，揭示了氢键、卤键和疏水相互作用在促进适当分子识别中的重要性。PFL 与不同蛋白质的结合相互作用能通常大于 FFL，是它们差异麻醉效果的重要决定因素。有趣的是，尽管羟基部分的氢键效应在丙泊酚中很突出，但 1-羟基被氟原子取代并没有阻止 FFL 通过卤键相互作用与蛋白质结合。因此，很明显，必须考虑多种特定相互作用，而不仅仅是氢键或卤键，才能解释由 PFL 和 FFL 引起的不同麻醉终点。还量化了配体-受体结合中关键残基的贡献，计算结果与许多可用的实验观察结果一致。这项工作将从稳健的理论角度为丙泊酚的麻醉作用机制提供补充见解。这不仅有助于解释实验观察结果，还有助于为进一步的实验和未来的药物设计提出工作假设。
