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Prediction of potential inhibitors against SARS-CoV-2 endoribonuclease: RNA immunity sensing
Journal of Biomolecular Structure and Dynamics ( IF 4.4 ) Pub Date : 2020-12-27 , DOI: 10.1080/07391102.2020.1863265
Nihad A M Al-Rashedi 1 , Murad G Munahi 2 , Laith Ah ALObaidi 1
Affiliation  

Abstract

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



中文翻译:

预测针对 SARS-CoV-2 核糖核酸内切酶的潜在抑制剂:RNA 免疫传感

摘要

世界卫生组织已将 COVID-19 疫情归类为由严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 引起的大流行,并宣布其为全球卫生紧急事件。重新利用具有最小副作用的药物是一种快速响应以防止 COVID-19 传播的方法。SARS-CoV-2 编码了几种 RNA 加工酶,这些酶对于单链 RNA 病毒来说是不寻常的和独特的,包括 Nsp15,一种六聚体核糖核酸内切酶,可立即区分切割尿苷的 3'。据报道,SARS-CoV-2 Nsp15 的结构与 SARS-CoV 和 MERS-CoV 的 Nsp15 核糖核酸内切酶同源,但它表现出的差异可能导致 SARS-CoV-2 的毒力更强。本研究旨在通过对包含 10,000 种已批准和实验药物的库进行基于分子对接的虚拟筛选,以确定针对 SARS-COV-2 Nsp15 的药物。分子对接结果显示 19 种药物表现出良好的 Nsp15 抑制能力。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,采用MM-PBSA方法验证结合亲和力。根据MD获得的结果,在MD模拟时间内,奥拉帕尼的复合物比对照抑制剂表现出更高的稳定性和更低的结合自由能。最后,

由 Ramaswamy H. Sarma 传达

更新日期:2020-12-27
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