DataSheet1_Remdesivir Strongly Binds to RNA-Dependent RNA Polymerase, Membrane Protein, and Main Protease of SARS-CoV-2: Indication From Molecular Modeling and Simulations.pdf

Development of new drugs is a time-taking and expensive process. Comprehensive efforts are being made globally toward the search of therapeutics against SARS-CoV-2. Several drugs such as remdesivir, favipiravir, ritonavir, and lopinavir have been included in the treatment regimen and shown effective results in several cases. Among the existing broad-spectrum antiviral drugs, remdesivir is found to be more effective against SARS-CoV-2. Remdesivir has broad-spectrum antiviral action against many single-stranded RNA viruses including pathogenic SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). In this study, we proposed that remdesivir strongly binds to membrane protein (Mprotein), RNA-dependent RNA polymerase (RDRP), and main protease (Mprotease) of SARS-CoV-2. It might show antiviral activity by inhibiting more than one target. It has been found that remdesivir binds to Mprotease, Mprotein, and RDRP with −7.8, −7.4, and −7.1 kcal/mol, respectively. The structure dynamics study suggested that binding of remdesivir leads to unfolding of RDRP. It has been found that strong binding of remdesivir to Mprotein leads to decrease in structural deviations and gyrations. Additionally, the average solvent-accessible surface area of Mprotein decreases from 127.17 to 112.12 nm2, respectively. Furthermore, the eigenvalues and the trace of the covariance matrix were found to be low in case of Mprotease–remdesivir, Mprotein–remdesivir, and RDRP–remdesivir. Binding of remdesivir to Mprotease, Mprotein, and RDRP reduces the average motions in protein due to its strong binding. The MMPBSA calculations also suggested that remdesivir has strong binding affinity with Mprotein, Mprotease, and RDRP. The detailed analysis suggested that remdesivir has more than one target of SARS-CoV-2.

新药的研发过程耗时且成本高昂。全球范围内，对针对SARS-CoV-2的治疗药物的搜索正作出全面努力。诸如瑞德西韦、法匹拉韦、利托那韦和洛匹那韦等药物已被纳入治疗方案，并在多起病例中显示出显著的治疗效果。在现有的广谱抗病毒药物中，瑞德西韦被发现对SARS-CoV-2具有更高的疗效。瑞德西韦对多种单链RNA病毒具有广谱抗病毒活性，包括致病性的SARS-CoV和中东呼吸综合征冠状病毒（MERS-CoV）。在本研究中，我们提出瑞德西韦能够与SARS-CoV-2的膜蛋白（M蛋白）、RNA依赖性RNA聚合酶（RDRP）和主要蛋白酶（M蛋白酶）强烈结合。它可能通过抑制多个靶点而表现出抗病毒活性。研究发现，瑞德西韦分别与M蛋白酶、M蛋白和RDRP结合的亲和力为-7.8、-7.4和-7.1 kcal/mol。结构动力学研究表明，瑞德西韦的结合导致RDRP的展开。研究发现，瑞德西韦与M蛋白的强烈结合导致结构偏差和扭曲的减少。此外，M蛋白的平均溶剂可及表面积从127.17 nm²降至112.12 nm²。进一步研究发现，M蛋白酶-瑞德西韦、M蛋白-瑞德西韦和RDRP-瑞德西韦的结合体系中，协方差矩阵的特征值和迹均较低。瑞德西韦与M蛋白酶、M蛋白和RDRP的结合降低了蛋白质的平均运动，这是由于其强烈的结合力所致。MMPBSA计算也表明，瑞德西韦与M蛋白、M蛋白酶和RDRP具有强烈的结合亲和力。详细分析表明，瑞德西韦对SARS-CoV-2具有多个靶点。