Laboratorio de Modelado Molecular, Bioinformática y Diseño de Fármacos de la Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico.
Laboratorio de Modelado Molecular, Bioinformática y Diseño de Fármacos de la Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico.
J Steroid Biochem Mol Biol. 2019 May;189:176-186. doi: 10.1016/j.jsbmb.2019.03.006. Epub 2019 Mar 6.
(-)-Epicatechin (Epi) has been demonstrated to activate pathways involved in GPER-stimulated nitric oxide (NO) production via endothelial NO synthase, known as the eNOS/NO pathway. Previous studies combining synthesis of four Epi derivatives demonstrated that Epi and Epi-prop, Epi-4-prop and Epi-5-prop were able to bind GPER by acting as GPER agonists, whereas docking studies allowed observation of structural details of the binding of these derivatives at the GPER binding site. However, due to the nature of past studies, the theoretical methods employed did not allow observation of structural and energetic details linked to ligand binding at the GPER binding site. In this contribution, we explore the structural and energetic changes coupling the binding of Epi and its four derivatives to GPER. To this end, MD simulations on the microsecond scale (1 μs) with an MMGBSA approach were used for each GPER-ligand complex. Energetic analysis demonstrated that incorporation of several aliphatic chains to Epi contributed to increasing the affinity towards the GPER binding site, thus helping to explain the experimental evidence. Structural analysis demonstrated that Epi, Epi-4-prop and Epi-5-prop share more similar interactions at GPER binding sites with similar conformational behavior than with Epi-prop and Epi-Ms. However, Epi-prop had additional residues that could explain its different but related biological effects.
（-）-表儿茶素（Epi）已被证明通过内皮型一氧化氮合酶（eNOS/NO 途径）激活与 GPER 刺激的一氧化氮（NO）产生有关的途径。先前结合合成四种 Epi 衍生物的研究表明，Epi 和 Epi-prop、Epi-4-prop 和 Epi-5-prop 能够通过充当 GPER 激动剂与 GPER 结合，而对接研究则允许观察这些衍生物在 GPER 结合位点的结合的结构细节。然而，由于过去研究的性质，所采用的理论方法无法观察到与配体在 GPER 结合位点结合相关的结构和能量细节。在这项研究中，我们探讨了将 Epi 及其四种衍生物与 GPER 结合相关的结构和能量变化。为此，使用 MMGBSA 方法对每个 GPER-配体复合物进行了微秒尺度（1 μs）的 MD 模拟。能量分析表明，将几个脂肪链掺入 Epi 有助于增加对 GPER 结合位点的亲和力，从而有助于解释实验证据。结构分析表明，Epi、Epi-4-prop 和 Epi-5-prop 在 GPER 结合位点上具有更多相似的相互作用，具有相似的构象行为，而与 Epi-prop 和 Epi-Ms 相比。然而，Epi-prop 有额外的残基可以解释其不同但相关的生物学效应。
