Cucurbitacins are present in some common vegetables as secondary metabolites and are used by the plants against harmful microbes. Exploration of this capability of natural product based substances against wide variety of microbes seems relevant due to the ease of availability of the resources and safety. In this regard, considering the current pandemic, the antiviral properties of these molecules with a subset of Cucurbitacin I structural derivatives have been screened. The inhibition potential of the phytochemicals was assessed by the stability of the protein–ligand complex formed with the nucleocapsid protein (PDB ID: 7CDZ) of SARS-CoV-2 by computational methods. The proposition of an alternate antiviral candidate that is cost-effective and efficient relative to existing formulations is the main objective of this work. Server-based molecular docking experiments revealed CBN19 (PubChem CID: 125125068) as a hit candidate among 101 test compounds, a reference molecule (K31), and 5 FDA-approved drugs in terms of binding affinities sorted out based on total energies. The molecular dynamics simulations (MDS) showed moderate stability of the protein-CBN19 complex as implied by various geometrical parameters RMSD, Rg, RMSF, SASA and hydrogen bond count. The ligand RMSD of 3.0 ± 0.5 Å, RMSF of Cα of protein with less than 5 Å, and smooth nature of SASA and Rg curves were calculated for the adduct. The binding free energy (− 47.19 ± 6.24 kcal/mol) extracted from the MDS trajectory using the MMGBSA method indicated spontaneity of the reaction between CBN19 and the protein. The multiple ADMET studies of the phytochemicals predicted some drug-like properties with minimal toxicity that mandate experimental verification. Based on all the preliminary in silico results, Cucurbitacin, CBN19 could be proposed as a potential inhibitor of nucleocapsid protein theoretically capable of curing the disease. The proposed molecule is recommended for further in vitro and in vivo trials in the quest to develop effective and alternate therapeutics from plant-based resources against COVID-19.

中文翻译：

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使用葫芦素 I 结构衍生物的 nCoV-19 疗法：计算机方法

葫芦素作为次生代谢物存在于一些常见蔬菜中，被植物用来对抗有害微生物。由于资源的容易获得性和安全性，探索基于天然产物的物质对抗多种微生物的这种能力似乎是相关的。在这方面，考虑到当前的大流行，已经筛选了这些具有葫芦素 I 结构衍生物子集的分子的抗病毒特性。通过计算方法，通过与 SARS-CoV-2 核衣壳蛋白（PDB ID：7CDZ）形成的蛋白质-配体复合物的稳定性来评估植物化学物质的抑制潜力。这项工作的主要目标是提出一种相对于现有制剂具有成本效益且高效的替代抗病毒候选药物。基于服务器的分子对接实验显示，就根据总能量排序的结合亲和力而言，CBN19（PubChem CID：125125068）是 101 种测试化合物、参考分子（K31）和 5 种 FDA 批准的药物中的热门候选药物。分子动力学模拟 (MDS) 显示蛋白质-CBN19 复合物具有中等稳定性，如各种几何参数 RMSD、Rg、RMSF、SASA 和氢键计数所暗示的。计算出加合物的配体 RMSD 为 3.0 ± 0.5 Å，Cα 的 RMSF 小于 5 Å，以及 SASA 和 Rg 曲线的平滑性。使用 MMGBSA 方法从 MDS 轨迹提取的结合自由能 (− 47.19 ± 6.24 kcal/mol) 表明 CBN19 和蛋白质之间的反应是自发的。对植物化学物质的多项 ADMET 研究预测了一些毒性最小的类似药物的特性，需要进行实验验证。根据所有初步的计算机结果，Cucurbitacin、CBN19 可以被认为是核衣壳蛋白的潜在抑制剂，理论上能够治愈该疾病。建议将该分子用于进一步的体外和体内试验，以寻求从植物资源中开发针对 COVID-19 的有效替代疗法。