Molecular Dynamics Simulations of the Interactions between Glial Cell Line-Derived Neurotrophic Factor Family Receptor GFRα1 and Small-Molecule Ligands,ACS Omega

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Molecular Dynamics Simulations of the Interactions between Glial Cell Line-Derived Neurotrophic Factor Family Receptor GFRα1 and Small-Molecule Ligands
ACS Omega ( IF 3.7 ) Pub Date : 2018-09-19 00:00:00 , DOI: 10.1021/acsomega.8b01524
Larisa Ivanova ₁ , Jaana Tammiku-Taul ₁ , Alfonso T García-Sosa ₁ , Yulia Sidorova ₂ , Mart Saarma ₂ , Mati Karelson ₁

Affiliation

The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) support the survival and functioning of various neuronal populations. Thus, they could be attractive therapeutic agents against a multitude of neurodegenerative diseases caused by progressive death of GFLs responsive neurons. Small-molecule ligands BT13 and BT18 show an effect on GDNF family receptor GFRα1 and RET receptor tyrosine kinase RetA function. Thus, their potential binding sites and interactions were explored in the GDNF–GFRα1–RetA complex using molecular docking calculations as well as molecular dynamics (MD) simulations. Three possible regions were examined: the interface between GDNF and GFRα1 (region A), the RetA interface with GFRα1 (region B), and a possible allosteric site in GFRα1 (region C). The results obtained by the docking calculations and the MD simulations indicate that the preferable binding occurs at the allosteric site. A less preferable binding site was detected on the RetA surface interfacing GFRα1. In the membrane-bound state of RetA this can enable compounds BT13 and BT18 to act as direct RetA agonists. The analysis of the MD simulations shows hydrogen bonds for BT13 and significant hydrophobic interactions with GFRα1 for BT13 and BT18 at the allosteric site.

中文翻译：

胶质细胞源性神经营养因子家族受体 GFRα1 与小分子配体相互作用的分子动力学模拟

胶质细胞源性神经营养因子 (GDNF) 家族配体 (GFL) 支持各种神经元群体的生存和功能。因此，它们可能是针对由 GFL 反应性神经元进行性死亡引起的多种神经退行性疾病的有吸引力的治疗剂。小分子配体 BT13 和 BT18 对 GDNF 家族受体 GFRα1 和 RET 受体酪氨酸激酶 RetA 功能有影响。因此，利用分子对接计算和分子动力学 (MD) 模拟，在 GDNF-GFRα1-RetA 复合物中探索了它们的潜在结合位点和相互作用。检查了三个可能的区域：GDNF 和 GFRα1 之间的界面（A 区）、RetA 与 GFRα1 的界面（B 区）以及 GFRα1 中可能的变构位点（C 区）。对接计算和MD模拟获得的结果表明，更好的结合发生在变构位点。在与 GFRα1 连接的 RetA 表面上检测到了不太优选的结合位点。在 RetA 的膜结合状态下，这可以使化合物 BT13 和 BT18 充当直接 RetA 激动剂。 MD 模拟分析显示 BT13 存在氢键，BT13 和 BT18 在变构位点与 GFRα1 存在显着的疏水相互作用。

更新日期：2018-09-19

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