Abstract

The global health emergency caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to alarming numbers of fatalities across the world. So far the researchers worldwide have not been able to discover a breakthrough in the form of a potent drug or an effective vaccine. Therefore, it is imperative to discover drugs to curb the ongoing menace. In silico approaches using FDA approved drugs can expedite the drug discovery process by providing leads that can be pursued. In this report, two drug targets, namely the spike protein and main protease, belonging to structural and non-structural class of proteins respectively, were utilized to carry out drug repurposing based screening. The exposed nature of the spike protein on the viral surface along with its instrumental role in host infection and the involvement of main protease in processing of polyproteins along with no human homologue make these proteins attractive drug targets. Interestingly, the screening identified a common high efficiency binding molecule named rutin. Further, molecular dynamics simulations in explicit solvent affirmed the stable and sturdy binding of rutin with these proteins. The decreased R_g value (4 nm for spike-rutin and 2.23 nm for main protease-rutin) and stagnant SASA analysis (485 nm/S²/N in spike-rutin and 152 nm/S2/N in main protease-rutin) for protein surface and its orientation in the exposed and buried regions suggests a strong binding interaction of the drug. Further, cluster analysis and secondary structure analysis of complex trajectories validated the conformational changes due to binding of rutin.

摘要

由严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 引起的全球卫生紧急情况已导致世界各地的死亡人数惊人。到目前为止，世界各地的研究人员还未能发现有效药物或有效疫苗形式的突破。因此，必须发现药物来遏制持续存在的威胁。使用 FDA 批准的药物的计算机方法可以通过提供可追踪的线索来加快药物发现过程。在本报告中，分别属于结构蛋白和非结构蛋白的两个药物靶点，即刺突蛋白和主蛋白酶，被用来进行基于药物再利用的筛选。刺突蛋白在病毒表面的暴露性质及其在宿主感染中的重要作用以及主要蛋白酶参与多蛋白加工而没有人类同源物，使这些蛋白质成为有吸引力的药物靶标。有趣的是，筛选确定了一种常见的高效结合分子，名为芦丁。此外，显式溶剂中的分子动力学模拟证实了芦丁与这些蛋白质的稳定和牢固的结合。减少的蛋白质的R _g值（spike-rutin 为 4 nm，主要蛋白酶-rutin 为 2.23 nm）和停滞的 SASA 分析（spike-rutin 中为 485 nm/S ² /N，主要蛋白酶-rutin 中为 152 nm/S2/N）表面及其在暴露和掩埋区域的方向表明药物的强结合相互作用。此外，复杂轨迹的聚类分析和二级结构分析验证了芦丁结合引起的构象变化。