Department of Biology, College of Science, Al-Muthanna University, Samawah, Iraq.
Department of Chemistry, College of Science, Al-Muthanna University, Samawah, Iraq.
J Biomol Struct Dyn. 2022 Jul;40(11):4879-4892. doi: 10.1080/07391102.2020.1863265. Epub 2020 Dec 27.
The World Health Organization has classified the COVID-19 outbreak a pandemic which is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) and declared it a global health emergency. Repurposing drugs with minimum side effects are one approach to quickly respond in attempt to prevent the spread of COVID-19. SARS-CoV-2 encodes several RNA processing enzymes that are unusual and unique for single-stranded RNA viruses, including Nsp15, a hexameric endoribonuclease that discriminatory cleaves immediately 3' of uridines. The structure of SARS-CoV-2 Nsp15 is reported to be homologous to that of the Nsp15 endoribonucleases of SARS-CoV and MERS-CoV, but it exhibits differences that may contribute to the greater virulence of SARS-CoV-2. This study aimed to identify drugs that targeted SARS-COV-2 Nsp15 using a molecular docking-based virtual screening of a library containing 10,000 approved and experimental drugs. The molecular docking results revealed 19 medications that demonstrated a good ability to inhibit Nsp15. Among all the candidated 19 drugs only five FDA approved drugs were used for further investigation by molecular dynamics simulation, the stability of Nsp15-ligand system was evaluated by calculating the RMSD, RMSF, radius of gyration and hydrogen bond profile. Furthermore, MM-PBSA method was employed to validate the binding affinity. According to the obtained results of MD, the complex of Olaparib was showed more stability and lower binding free energy than the control inhibitor during MD simulation time. Finally, we suggest that Olaparib is a potential drug for treating patients infected with SARS-CoV-2 and provide insight into the host immune response to viral RNA.Communicated by Ramaswamy H. Sarma.
世界卫生组织已将 COVID-19 疫情宣布为大流行，该疫情由严重急性呼吸系统综合症冠状病毒 2（SARS-CoV-2）引起，并宣布其为全球卫生紧急事件。重新利用副作用最小的药物是快速应对以试图阻止 COVID-19 传播的一种方法。SARS-CoV-2 编码几种 RNA 加工酶，这些酶对单链 RNA 病毒来说是不寻常和独特的，包括 Nsp15，一种六聚体内切核糖核酸酶，可特异性切割尿嘧啶的 3'端。据报道，SARS-CoV-2 Nsp15 的结构与 SARS-CoV 和 MERS-CoV 的 Nsp15 内切核糖核酸酶同源，但它表现出的差异可能导致 SARS-CoV-2 的毒力更强。本研究旨在使用包含 10000 种已批准和实验性药物的库进行基于分子对接的虚拟筛选，以鉴定靶向 SARS-COV-2 Nsp15 的药物。分子对接结果显示有 19 种药物具有良好的抑制 Nsp15 的能力。在所有候选的 19 种药物中，只有 5 种获得 FDA 批准的药物用于通过分子动力学模拟进一步研究，通过计算 RMSD、RMSF、回转半径和氢键分布来评估 Nsp15-配体系统的稳定性。此外，还采用 MM-PBSA 方法验证结合亲和力。根据 MD 获得的结果，在 MD 模拟过程中，奥拉帕利与对照抑制剂相比，复合物表现出更高的稳定性和更低的结合自由能。最后，我们建议奥拉帕利是治疗感染 SARS-CoV-2 的患者的潜在药物，并为了解宿主对病毒 RNA 的免疫反应提供了线索。
