Samsonov Sergey A, Freza Sylwia, Zsila Ferenc
Laboratory of Molecular Modeling, Faculty of Chemistry, University of Gdańsk, ul. Wita Stwosza 63, 80-308, Gdańsk, Poland.
Laboratory of Quantum Chemistry, Faculty of Chemistry, University of Gdańsk, ul. Wita Stwosza 63, 80-308, Gdańsk, Poland.
Carbohydr Res. 2019 Aug 1;482:107742. doi: 10.1016/j.carres.2019.107742. Epub 2019 Jul 11.
Glycosaminoglycans (GAGs) is a particular class of linear anionic periodic polysaccharides, which play a key role in many cell signaling processes in the extracellular matrix by direct interactions with multiple proteins targets. Because of their periodic nature resulting in experimental challenges to study these molecules, computational approaches recently proved to be successful in complementing the experiments aimed to understand GAG interactions. However, the aspect of GAG binding of small, pharmacologically active molecules is still essentially understudied despite its significance. In this work, we apply computational approaches to rigorously characterize the interactions between GAGs and two trypanosoma active DNA targeting agents, berenil and pentamidine, which mainly differ in the structure of their intramolecular linkers connecting two benzamidine moieties. We thoroughly analyze their binding to heparin and chondroitin 6-sulfate in terms of dynamics, energetics and properties of π-stacked oligomeric structures of the drug molecules formed upon GAG association. Our work contributes to the general understanding of biologically relevant interactions between GAGs and small molecules which has potential impact in drug pharmacology and related therapeutic modalities.
糖胺聚糖（GAGs）是一类特殊的线性阴离子周期性多糖，通过与多种蛋白质靶点直接相互作用，在细胞外基质的许多细胞信号传导过程中发挥关键作用。由于其周期性性质给研究这些分子带来了实验挑战，最近计算方法已被证明在补充旨在理解GAG相互作用的实验方面取得了成功。然而，尽管其具有重要意义，但小分子、药理活性分子与GAG结合的方面仍基本未被研究。在这项工作中，我们应用计算方法来严格表征GAG与两种锥虫活性DNA靶向剂贝尼尔和喷他脒之间的相互作用，这两种药物主要在连接两个苯甲脒部分的分子内连接体结构上有所不同。我们从动力学、能量学以及GAG结合时形成的药物分子π堆积寡聚结构的性质方面，深入分析了它们与肝素和硫酸软骨素6 - 硫酸盐的结合情况。我们的工作有助于全面理解GAG与小分子之间的生物学相关相互作用，这对药物药理学及相关治疗方式具有潜在影响。
