Accessing COVID-19 vaccines is a challenge despite successful clinical trials. This burdens the COVID-19 treatment gap, thereby requiring accelerated discovery of anti-SARS-CoV-2 agents. This study explored the potential of anti-HIV reverse transcriptase (RT) phytochemicals as inhibitors of SARS-CoV-2 non-structural proteins (nsps) by targeting in silico key sites in the structures of SARS-CoV-2 nsps. One hundred four anti-HIV phytochemicals were subjected to molecular docking with nsp3, 5, 10, 12, 13, 15, and 16. Top compounds in complex with the nsps were investigated further through molecular dynamics. The drug-likeness and ADME (absorption, distribution, metabolism, and excretion) properties of the top compounds were also predicted using SwissADME. Their toxicity was likewise determined using OSIRIS Property Explorer. Among the top-scoring compounds, the polyphenolic functionalized natural products comprised of biflavones 1, 4, 11, 13, 14, 15; ellagitannin 9; and bisisoquinoline alkaloid 19 were multi-targeting and exhibited strongest binding affinities to at least two nsps (binding energy = − 7.7 to − 10.8 kcal/mol). The top ligands were stable in complex with their target nsps as determined by molecular dynamics. Several top-binding compounds were computationally druggable, showed good gastrointestinal absorptive property, and were also predicted to be non-toxic. Twenty anti-HIV RT phytochemicals showed multi-targeting inhibitory potential against SARS-CoV-2 non-structural proteins 3, 5, 10, 12, 13, 15, and 16. Our results highlight the importance of polyhydroxylated aromatic substructures for effective attachment in the binding/catalytic sites of nsps involved in post-translational mechanism pathways. As such with the nsps playing vital roles in viral pathogenesis, our findings provide inspiration for the design and discovery of novel anti-COVID-19 drug prototypes.

中文翻译：

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抗 HIV 逆转录酶植物多酚天然产物，对 SARS-CoV-2 发病机制中至关重要的七种非结构蛋白具有计算机抑制特性


尽管临床试验取得了成功，但获得 COVID-19 疫苗仍是一项挑战。这加重了 COVID-19 治疗缺口，因此需要加速发现抗 SARS-CoV-2 药物。本研究通过计算机模拟靶向 SARS-CoV-2 非结构蛋白 (nsps) 结构中的关键位点，探讨了抗 HIV 逆转录酶 (RT) 植物化学物质作为 SARS-CoV-2 非结构蛋白 (nsps) 抑制剂的潜力。一百四种抗 HIV 植物化学物质与 nsp3、5、10、12、13、15 和 16 进行了分子对接。通过分子动力学进一步研究了与 nsp 复合的顶级化合物。还使用 SwissADME 预测了顶级化合物的药物相似性和 ADME（吸收、分布、代谢和排泄）特性。它们的毒性同样是使用 OSIRIS Property Explorer 确定的。在得分最高的化合物中，多酚功能化天然产物包括双黄酮1、4、11、13、14、15；鞣花单宁9;和双异喹啉生物碱 19 是多靶点的，并且对至少两个 nsps 表现出最强的结合亲和力（结合能 = − 7.7 至 − 10.8 kcal/mol）。根据分子动力学测定，顶部配体与其目标 nsps 形成复合物是稳定的。几种顶部结合化合物通过计算可成药，表现出良好的胃肠道吸收特性，并且预计是无毒的。二十种抗 HIV RT 植物化学物质对 SARS-CoV-2 非结构蛋白 3、5、10、12、13、15 和 16 显示出多靶点抑制潜力。我们的结果强调了多羟基化芳香族亚结构对于有效附着的重要性参与翻译后机制途径的 nsp 的结合/催化位点。 因此，nsp 在病毒发病机制中发挥着至关重要的作用，我们的研究结果为设计和发现新型抗 COVID-19 药物原型提供了灵感。