datasheet1_Discovering Potential RNA Dependent RNA Polymerase Inhibitors as Prospective Drugs Against COVID-19: An in silico Approach.pdf

COVID-19, caused by Severe Acute Respiratory Syndrome Corona Virus 2, is declared a Global Pandemic by WHO in early 2020. In the present situation, though more than 180 vaccine candidates with some already approved for emergency use, are currently in development against SARS-CoV-2, their safety and efficacy data is still in a very preliminary stage to recognize them as a new treatment, which demands an utmost emergency for the development of an alternative anti-COVID-19 drug sine qua non for a COVID-19 free world. Since RNA-dependent RNA polymerase (RdRp) is an essential protein involved in replicating the virus, it can be held as a potential drug target. We were keen to explore the plant-based product against RdRp and analyze its inhibitory potential to treat COVID-19. A unique collection of 248 plant compounds were selected based on their antiviral activity published in previous literature and were subjected to molecular docking analysis against the catalytic sub-unit of RdRp. The docking study was followed by a pharmacokinetics analysis and molecular dynamics simulation study of the selected best-docked compounds. Tellimagrandin I, SaikosaponinB2, Hesperidin and (-)-Epigallocatechin Gallate were the most prominent ones that showed strong binding affinity toward RdRp. All the compounds mentioned showed satisfactory pharmacokinetics properties and remained stabilized at their respective binding sites during the Molecular dynamics simulation. Additionally, we calculated the free-binding energy/the binding properties of RdRp-ligand complexes with the connection of MM/GBSA. Interestingly, we observe that SaikosaponinB2 gives the best binding affinity (∆Gbinding = −42.43 kcal/mol) in the MM/GBSA assay. Whereas, least activity is observed for Hesperidin (∆Gbinding = −22.72 kcal/mol). Overall our study unveiled the feasibility of the SaikosaponinB2 to serve as potential molecules for developing an effective therapy against COVID-19 by inhibiting one of its most crucial replication proteins, RdRp.

由严重急性呼吸综合征冠状病毒2型（Severe Acute Respiratory Syndrome Coronavirus 2，SARS-CoV-2）引发的COVID-19，于2020年初被世界卫生组织（World Health Organization，WHO）列为全球大流行病。当前尽管已有超180种针对SARS-CoV-2的疫苗候选物，其中部分已获批紧急使用，但相关候选物的安全性与有效性数据仍处于初步阶段，尚未能被认定为成熟的治疗方案，这迫切需要开发可替代的抗COVID-19药物，而这是实现无新冠疫情世界的不可或缺的条件。RNA依赖的RNA聚合酶（RNA-dependent RNA polymerase，RdRp）是病毒复制过程中的必需蛋白，因此可作为潜在的药物作用靶点。本研究旨在探索植物来源的抗RdRp制剂，并分析其用于治疗COVID-19的抑制潜力。研究人员基于既往文献报道的抗病毒活性，筛选得到248种植物来源化合物，并针对RdRp的催化亚基开展分子对接分析。对接研究完成后，对筛选出的最优对接化合物进行药代动力学分析与分子动力学模拟研究。单宁酰基葡萄糖苷I（Tellimagrandin I）、柴胡皂苷B2（Saikosaponin B2）、橙皮苷（Hesperidin）以及(-)-表没食子儿茶素没食子酸酯[(-)-Epigallocatechin Gallate]是表现最为突出的化合物，它们与RdRp展现出极强的结合亲和力。上述所有化合物均具备良好的药代动力学特性，且在分子动力学模拟过程中可稳定结合于各自的靶点结合位点。此外，本研究通过分子力学/广义玻恩表面积法（Molecular Mechanics/Generalized Born Surface Area，MM/GBSA）计算了RdRp-配体复合物的自由结合能与结合特性。值得注意的是，在MM/GBSA检测中，柴胡皂苷B2展现出最优的结合亲和力（结合自由能∆Gbinding = −42.43 kcal/mol），而橙皮苷的结合活性最弱（∆Gbinding = −22.72 kcal/mol）。综上，本研究揭示了柴胡皂苷B2作为潜在候选分子的可行性，其可通过抑制新冠病毒关键复制蛋白RdRp，开发出有效的抗COVID-19治疗手段。