COVID-19目前被认为是第九大致命的流行病,通过与感染者直接或间接接触传播。它给许多国家的财政和医疗保健资源带来了持续的压力。为了应对这一挑战,迫切需要开发新的潜在治疗药物来治疗这种疾病。为了确定潜在的抗病毒剂作为SARS-CoV-2的新型双重抑制剂,我们从12种选定的药用抗病毒植物中检索了404生物碱,并对其进行了虚拟筛选,以对抗SARS-CoV-2的两种必需蛋白的著名催化位点和有利的相互作用残基,即,主要蛋白酶和刺突糖蛋白。根据对接分数,对12种具有双重抑制潜力的代谢物进行药物相似度,生物活性评分,和类似药物的能力分析。这些分析包括配体-受体稳定性和靶蛋白潜在活性位点的相互作用,通过对三种铅代谢物的分子动力学模拟进行分析和证实。我们还使用分子力学技术对关键的SARS-CoV-2蛋白抑制剂进行了详细的结合自由能分析,以揭示它们的相互作用动力学和稳定性。总的来说,我们的结果表明,12种生物碱,即,阿杜西汀Y,evodiamideC,麦角醇,Hayatinine,(+)-高芳啉,乙苯硫醚C,N,α-L-鼠李糖基长春胺,pelosine,利血平,toddalidimerine,Toddayanis,和zanthocadinanine,根据它们与靶蛋白的相互作用作为代谢物入围。与标准品相比,所有12种铅代谢物均表现出较高的未结合分数,因此分布更大。特别是,阿杜西汀Y显示出较高的对接分数,但表现出非自发结合谱。相比之下,麦角苷和evodiamideC在分子动力学模拟中显示出良好的结合相互作用和优越的稳定性。Ergosine在几个关键的制药指标中表现出卓越的性能。药代动力学评估显示,麦角苷表现出明显的生物活性,吸收好,和最佳生物利用度。此外,预计不会引起皮肤敏感,并且发现非肝毒性。重要的是,由于其强大的结合亲和力和类似药物的能力,麦角苷和evodiamideC成为SARS-CoV-2双重抑制的优异药物候选物,与已知的抑制剂如N3和莫那普拉韦相当。这项研究受到其计算机性质的限制,需要未来的体外和体内研究来证实这些发现。
COVID-19 is currently considered the ninth-deadliest pandemic, spreading through direct or indirect contact with infected individuals. It has imposed a consistent strain on both the financial and healthcare resources of many countries. To address this challenge, there is a pressing need for the development of new potential therapeutic agents for the treatment of this disease. To identify potential antiviral agents as novel dual inhibitors of SARS-CoV-2, we retrieved 404 alkaloids from 12 selected medicinal antiviral plants and virtually screened them against the renowned catalytic sites and favorable interacting residues of two essential proteins of SARS-CoV-2, namely, the main protease and spike glycoprotein. Based on docking scores, 12 metabolites with dual inhibitory potential were subjected to drug-likeness, bioactivity scores, and drug-like ability analyses. These analyses included the ligand-receptor stability and interactions at the potential active sites of target proteins, which were analyzed and confirmed through molecular dynamic simulations of the three lead metabolites. We also conducted a detailed binding free energy analysis of pivotal SARS-CoV-2 protein inhibitors using molecular mechanics techniques to reveal their interaction dynamics and stability. Overall, our results demonstrated that 12 alkaloids, namely, adouetine Y, evodiamide C, ergosine, hayatinine, (+)-homoaromoline, isatithioetherin C, N,alpha-L-rhamnopyranosyl vincosamide, pelosine, reserpine, toddalidimerine, toddayanis, and zanthocadinanine, are shortlisted as metabolites based on their interactions with target proteins. All 12 lead metabolites exhibited a higher unbound fraction and therefore greater distribution compared with the standards. Particularly, adouetine Y demonstrated high docking scores but exhibited a nonspontaneous binding profile. In contrast, ergosine and evodiamide C showed favorable binding interactions and superior stability in molecular dynamics simulations. Ergosine demonstrated exceptional performance in several key pharmaceutical metrics. Pharmacokinetic evaluations revealed that ergosine exhibited pronounced bioactivity, good absorption, and optimal bioavailability. Additionally, it was predicted not to cause skin sensitivity and was found to be non-hepatotoxic. Importantly, ergosine and evodiamide C emerged as superior drug candidates for dual inhibition of SARS-CoV-2 due to their strong binding affinity and drug-like ability, comparable to known inhibitors like N3 and molnupiravir. This study is limited by its in silico nature and demands the need for future in vitro and in vivo studies to confirm these findings.