Exploration of alternate therapeutic remedies in Ebola virus disease: the case of reported antiviral phytochemical derived from the leaves Spondias Mombin Linn
Exploration of alternate therapeutic remedies in Ebola virus disease: the case of reported antiviral phytochemical derived from the leaves Spondias Mombin Linn
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DOI：
10.1007/s13596-021-00603-5
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发表时间：
2021-08-07
影响因子：
2
通讯作者：
Nlooto, Manimbulu
中科院分区：
文献类型：
--
作者：
Boadu, Akwasi;Karpoormath, Rajshekhar;Nlooto, Manimbulu
引起埃博拉病毒病的六种埃博拉病毒（EBOV）中最常见和最致命的是扎伊尔EBOV，感染患者的死亡率约为90%。本研究旨在使用计算机辅助药物设计方法从报道的具有抗病毒特性的植物化学化合物中鉴定潜在的EBOV分泌糖蛋白（sGP）抑制剂。研究结果表明，老鹳草素是最有前途的抑制剂候选物，在进行100 ns分子动力学模拟后，使用分子力学/泊松-玻尔兹曼表面积方法，表现出最高的对接得分为-9.3 kcal/mol，估计结合自由能（Δ Gbind）为-30.34 kcal/mol。结合动力学表明，存在一个广泛的相互作用网络，将天竺葵素锚定在EBOV sGP结合口袋内，从而产生较强的结合自由能。与老鹳草素相互作用的关键残基包括：TRP 104、ALA 205、ARG 136、ARG 134、ASP 208和THR 206。药代动力学分析表明，虽然老鹳草素违反Lipinski的规则的5个典型的大多数天然化合物，大的分子量表明，它的合成碎片更小，更简单的化合物可以增加其生物活性和药代动力学特征。总之，所产生的药效团模型显示，老鹳草素上的三个芳环、一个疏水环和几个氢供体/受体对于其对EBOV sGP的抑制性结合至关重要。因此，根据进一步的实验验证，本报告中提供的见解将天竺葵素作为EBOV sGP的潜在抑制剂候选物。
The most common and lethal of the six strains of Ebola viruses (EBOV) causing the Ebolavirus disease is the Zaire EBOV and has an approximately 90% mortality rate of infected patients. This study aimed to identify potential EBOV secreted Glycoprotein (sGP) inhibitors from reported phytochemical compounds with antiviral properties in leaf extracts of Spondias mombin Linn using computer-aided drug design approaches. Findings from the study indicated that Geraniin is the most promising inhibitor candidate, exhibiting the highest docking score of - 9.3 kcal/mol with estimated binding free energy (Delta Gbind) of - 30.34 kcal/mol using Molecular Mechanics/Poisson-Boltzmann Surface Area approach after a 100 ns Molecular Dynamic simulation was performed. The binding dynamics of Geraniin showed that there was an extensive network of interactions that anchored Geraniin within the EBOV sGP binding pocket accounting for the strong binding free energy. Crucial residues that interacted with Geraniin included; TRP104, ALA205, ARG136, ARG134, ASP208 and THR206. The pharmacokinetic analysis revealed that although Geraniin violated Lipinski's rule of 5 typical of most natural compounds, the large molecular weight suggests that its synthetic fragmentation to smaller and simpler compounds could increase its bioactivity and pharmacokinetic features. In sum, a pharmacophore model generated showed that three aromatic rings, a hydrophobic ring and several hydrogen donors/acceptors on Geraniin were crucial towards its inhibitory binding on EBOV sGP. Therefore, subject to further experimental validation the insights provided in this report present Geraniin as a potential inhibitor candidate of EBOV sGP.