Metwaly Ahmed M, El-Fakharany Esmail M, Alsfouk Aisha A, Ibrahim Ibrahim M, Elkaeed Eslam B, Eissa Ibrahim H
Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
Protein Research Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), City of Scientific Research and Technological Applications (SRTA-City), New Borg El-Arab City, Alexandria, 21934, Egypt.
Curr Med Chem. 2025 Jan 2. doi: 10.2174/0109298673339634241210151734.
In our quest to identify potent inhibitors against SARS-CoV-2, an extensive investigation was conducted for the binding and inhibitory efficacy of Rutin against nine SARS-CoV-2 proteins.
The first step of our analysis involved a comprehensive examination of structural similarity among the co-crystallized ligands associated with those proteins. A substantial structural similarity was observed between Rutin and Remdesivir, the ligand of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). This similarity was validated through a flexible alignment study. Molecular docking studies, involving superimposition, revealed a notable resemblance in the mode of binding between Rutin and Remdesivir inside the active site of the RdRp. A 200 ns molecular dynamics (MD) simulation confirmed that the RdRp-Rutin complex is more stable than the RdRp-Remdesivir complex.
The MM-GBSA studies showed that Rutin had much more favorable binding energies, with a significantly lower value of -7.76 kcal/mol compared to Remdesivir's -2.15 kcal/mol. This indicates that the RdRp-Rutin binding is more robust and stable PLIP and ProLIF studies helped clarify the 3D binding interactions and confirmed the stable binding seen in MD simulations. PCAT gave more insights into the dynamic behavior of the RdRp-Rutin complex. in vitro tests showed that Rutin has a strong inhibitory effect on RdRp with an IC50 of 60.09 nM, significantly outperforming Remdesivir, which has an IC50 of 24.56 µM. Remarkably, against SARS-CoV-2, Rutin showed a superior in vitro IC50 of 0.598 µg/ml compared to Remdesivir (12.47 µg/ml).
The values of the selectivity index underscored the exceptional margin of safety of Rutin (SI: 1078) compared to Remdesivir (SI: 5.8). In conclusion, our comprehensive analysis indicates Rutin's promising potential as a potent SARS-CoV-2 RdRp inhibitor, providing a valuable insight for developing an effective COVID-19 treatment.
在我们寻找针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的有效抑制剂的过程中，对芦丁针对九种SARS-CoV-2蛋白的结合和抑制效果进行了广泛研究。
我们分析的第一步涉及全面检查与这些蛋白相关的共结晶配体之间的结构相似性。在芦丁与瑞德西韦（SARS-CoV-2 RNA依赖性RNA聚合酶（RdRp）的配体）之间观察到显著的结构相似性。这种相似性通过灵活比对研究得到验证。分子对接研究（包括叠加）揭示了芦丁与瑞德西韦在RdRp活性位点内的结合模式有显著相似之处。一项200纳秒的分子动力学（MD）模拟证实，RdRp-芦丁复合物比RdRp-瑞德西韦复合物更稳定。
MM-GBSA研究表明，芦丁具有更有利的结合能，与瑞德西韦的-2.15千卡/摩尔相比，其值显著更低，为-7.76千卡/摩尔。这表明RdRp-芦丁的结合更强健且稳定。PLIP和ProLIF研究有助于阐明三维结合相互作用，并证实了MD模拟中所见的稳定结合。PCAT对RdRp-芦丁复合物的动态行为提供了更多见解。体外试验表明，芦丁对RdRp具有强烈抑制作用，IC50为60.09纳摩尔，显著优于瑞德西韦，其IC50为24.56微摩尔。值得注意的是，针对SARS-CoV-2，芦丁的体外IC50为0.598微克/毫升，优于瑞德西韦（12.47微克/毫升）。
选择性指数的值强调了芦丁（SI：1078）与瑞德西韦（SI：5.8）相比具有卓越的安全性。总之，我们的综合分析表明芦丁作为一种有效的SARS-CoV-2 RdRp抑制剂具有广阔的潜力，为开发有效的COVID-19治疗方法提供了有价值的见解。
