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首页> 外文期刊>Molecular informatics >Evaluation of Adamantane Derivatives as Inhibitors of Dengue Virus mRNA Cap Methyltransferase by Docking and Molecular Dynamics Simulations
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Evaluation of Adamantane Derivatives as Inhibitors of Dengue Virus mRNA Cap Methyltransferase by Docking and Molecular Dynamics Simulations

机译：通过对接和分子动力学模拟评估金刚烷衍生物作为登革热病毒mRNA帽甲基转移酶抑制剂

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Abstract: Binding of the Dengue virus 5-adenosyl-L-methio-nine (AdoMet)-dependent mRNA cap methyltransferase (NS5MTase_(DV)) with adamantane derivatives was explored using molecular modeling methods and (nucleoside-2'O)-methyltransferase bioassay. The studied compounds include urea derivatives of adamantane and the antiviral drugs amantadine and rimantadine. The urea derivatives of adamantanes had previously been identified as inhibitors of NS5MTase_(DV). The docking simulations using GOLD, Glide, and Dock give consistent binding modes and binding affinities of adamantanes in the AdoMet-binding site of NS5MTase_(DV) and, in particular, yield similar positions for the previously found inhibitors. Combined, they perfectly correspond to the bioassay measurements of nucleoside-2'O-methyltransferase activity of NS5Tase_(DV), which confirmed inhibitory properties of the active urea adamantane but did not show inhibitory activity for amantadine and rimantadine. We also employed microscopic molecular dynamics (MD) simulations and a linear interaction energy (LIE) method to verify the docking results. The MD/LIE binding free energies of selected protein-inhibitor complexes agree overall with the binding affinities from docking and demonstrate that amantadine and rimantadine only weakly bind at the explored site. The MD simulations also demonstrated the flexible character of a protein loop that is located between the beta2 and beta3 strands and is part of the AdoMet-binding pocket of NS5MTase_(DV).
机译：摘要：利用分子建模方法和（nucleoside-2'O）-甲基转移酶生物测定法，探讨了登革热病毒5-腺苷-L-甲硫氨酸（AdoMet）依赖性mRNA帽甲基转移酶（NS5MTase_（DV））与金刚烷衍生物的结合。 。研究的化合物包括金刚烷的脲衍生物以及抗病毒药物金刚烷胺和金刚乙胺。先前已将金刚烷的脲衍生物鉴定为NS5MTase_（DV）的抑制剂。使用GOLD，Glide和Dock的对接模拟在NS5MTase_（DV）的AdoMet结合位点提供了一致的结合模式和金刚烷的结合亲和力，尤其是对于先前发现的抑制剂产生了相似的位置。结合起来，它们完全对应于NS5Tase_（DV）核苷2'O-甲基转移酶活性的生物测定测量结果，证实了活性尿素金刚烷的抑制特性，但对金刚烷胺和金刚烷胺没有抑制活性。我们还采用了微观分子动力学（MD）模拟和线性相互作用能（LIE）方法来验证对接结果。所选蛋白质-抑制剂复合物的MD / LIE结合自由能总体上与对接的结合亲和力一致，并证明金刚烷胺和金刚烷胺仅在勘探位点弱结合。 MD模拟还证明了位于β2和β3链之间的蛋白环的柔性特征，该蛋白环是NS5MTase_（DV）的AdoMet结合口袋的一部分。

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