Faculty of Science, University of Split, Ruđera Boškovića 33, HR-21000 Split, Croatia.
Center of Excellence for Science and Technology-Integration of Mediterranean Region (STIM) at Interdisciplinary Center for Advanced Sciences and Technology (ICAST), University of Split, Meštrovićevo šetalište 45, HR-21000 Split, Croatia.
Int J Mol Sci. 2021 Feb 28;22(5):2415. doi: 10.3390/ijms22052415.
Interleukin-6 (IL-6) is involved in physiological and pathological processes. Different pharmacological agents have been developed to block IL-6 deleterious effects and to recover homeostatic IL-6 signaling. One of the proposed nanostructures in pre-clinical investigations which reduced IL-6 concentrations is polyglycerol dendrimer, a nano-structure with multiple sulfate groups. The aim of the present study was to uncover the type of binding between critical positions in the human IL-6 structure available for binding dPGS and compare it with heparin sulfate binding. We studied these interactions by performing docking simulations of dPGS and heparins with human IL-6 using AutoDock Vina. These molecular docking analyses indicate that the two ligands have comparable affinities for the positively charged positions on the surface of IL-6. All-atom molecular dynamics simulations (MD) employing Gromacs were used to explore the binding sites and binding strengths. Results suggest two major binding sites and show that the strengths of binding are similar for heparin and dPGS (-5.5-6.4 kcal/ mol). dPGS or its analogs could be used in the therapeutic intervention in sepsis and inflammatory disorders to reduce unbound IL-6 in the plasma or tissues and its binding to the receptors. We propose that analogs of dPGS could specifically block IL-6 binding in the desired signaling mode and would be valuable new probes to establish optimized therapeutic intervention in inflammation.
白细胞介素-6（IL-6）参与生理和病理过程。已经开发出不同的药理学制剂来阻断 IL-6 的有害作用并恢复体内平衡的 IL-6 信号。在临床前研究中提出的一种减少 IL-6 浓度的纳米结构是聚甘油树突，这是一种具有多个硫酸基团的纳米结构。本研究的目的是揭示人 IL-6 结构中可与 dPGS 结合的关键位置之间的结合类型，并将其与肝素硫酸盐结合进行比较。我们使用 AutoDock Vina 对 dPGS 和肝素与人 IL-6 进行对接模拟，研究了这些相互作用。这些分子对接分析表明，两种配体对 IL-6 表面带正电荷的位置具有相当的亲和力。使用 Gromacs 进行全原子分子动力学模拟（MD）以探索结合位点和结合强度。结果表明存在两个主要结合位点，并表明肝素和 dPGS 的结合强度相似（-5.5-6.4 kcal/mol）。dPGS 或其类似物可用于脓毒症和炎症性疾病的治疗干预，以减少血浆或组织中未结合的 IL-6 及其与受体的结合。我们提出，dPGS 的类似物可以特异性地阻断所需信号模式中的 IL-6 结合，并且将是建立炎症优化治疗干预的有价值的新探针。
