2019年冠状病毒病(COVID-19)是一种大流行,严重构成了巨大的健康挑战,夺去了数百万人的生命。尽管已经生产了疫苗来阻止这种疾病的传播,死亡率仍然很高,因为用于治疗的药物具有治疗挑战。严重急性呼吸道综合征冠状病毒2(SARS-CoV-2),导致这种疾病的病毒,有一系列潜在的治疗靶点。其中包括弗林蛋白酶,在病毒的刺突蛋白上有一个切割位点。切割位点促进病毒通过细胞-细胞融合进入人细胞。弗林蛋白酶在疾病致病性中的这种关键参与使其成为针对该病毒的可行治疗策略。这项研究采用了使用HYBRID和AutoDockVina的共识对接方法,实际上筛选了针对人类弗林蛋白酶(PDB:4RYD)的3942种非洲来源的天然产物化合物的预过滤文库。在满足-7kcal的分子对接截止值之后,选择这些化合物中的20个作为命中。mol-1,姿态对准检查,并具有良好的弗林蛋白酶-配体相互作用。从受试者操作特征(ROC)曲线计算出0.72的曲线下面积(AUC)值,和Boltzmann增强的ROC曲线判别(BEDROC)值为0.65,表明AutoDockVina是选择该靶标活性物质的合理工具。这些命中中的七个被认为是潜在的线索,它们与催化三联体残基Ser368,His194和Asp153以及活性位点中的其他必需残基发生了键合相互作用,合理的结合自由能介于-189和-95kJ/mol之间。分子力学泊松-玻尔兹曼表面积(MM-PBSA)计算以及良好的ADME/Tox特性。这些分子也被预测为抗病毒分子,抗炎,膜渗透性抑制剂,RNA合成抑制剂,细胞保护,和肝脏保护,可能的活性(Pa)高于0.5,可能的不活动值低于0.1。其中一些还具有抗流感活性。流感病毒在进入人细胞的方式上与SARS-CoV-2有许多相似之处,因为两者都由弗林蛋白酶促进。Pinobanksin3-(E)-咖啡酸盐,潜在的线索之一是蜂胶化合物。在先前的研究中,蜂胶化合物对SARS-CoV-2的ACE2,TMPRSS2和PAK1信号通路具有抑制作用。同样,槲皮苷在结构上与异槲皮素相似,目前正在临床试验中,作为COVID-19的可能药物。
UNASSIGNED:在线版本包含补充材料,可在10.1007/s11224-022-02056-1获得。
The coronavirus disease 2019 (COVID-19) is a pandemic that has severely posed substantial health challenges and claimed millions of lives. Though vaccines have been produced to stem the spread of this disease, the death rate remains high since drugs used for treatment have therapeutic challenges. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes the disease, has a slew of potential therapeutic targets. Among them is the furin protease, which has a cleavage site on the virus\'s spike protein. The cleavage site facilitates the entry of the virus into human cells via cell-cell fusion. This critical involvement of furin in the disease pathogenicity has made it a viable therapeutic strategy against the virus. This study employs the
consensus docking approach using HYBRID and AutoDock Vina to virtually screen a pre-filtered library of 3942 natural product compounds of African origin against the human furin protease (PDB: 4RYD). Twenty of these compounds were selected as hits after meeting molecular docking cut-off of - 7 kcal.mol-1, pose alignment inspection, and having favorable furin-ligand interactions. An area under the curve (AUC) value of 0.72 was computed from the receiver operator characteristic (ROC) curve, and Boltzmann-enhanced discrimination of the ROC curve (BEDROC) value of 0.65 showed that AutoDock Vina was a reasonable tool for selecting actives for this target. Seven of these hits were proposed as potential leads having had bonding interactions with catalytic triad residues Ser368, His194, and Asp153, and other essential residues in the active site with plausible binding free energies between - 189 and - 95 kJ/mol from the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations as well as favorable ADME/Tox properties. The molecules were also predicted as antiviral, anti-inflammatory, membrane permeability inhibitors, RNA synthesis inhibitors, cytoprotective, and hepatoprotective with probable activity (Pa) above 0.5 and probable inactivity values below 0.1. Some of them also have anti-influenza activity. Influenza virus has many similarities with SARS-CoV-2 in their mode of entry into human cells as both are facilitated by the furin protease. Pinobanksin 3-(E)-caffeate, one of the potential leads is a propolis compound. Propolis compounds have shown inhibitory effects against ACE2, TMPRSS2, and PAK1 signaling pathways of SARS-CoV-2 in previous studies. Likewise, quercitrin is structurally similar to isoquercetin, which is currently in clinical trials as possible medication for COVID-19.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s11224-022-02056-1.