Uddin Reaz, Jalal Khurshid, Khan Kanwal, Ul-Haq Zaheer
Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Lab 103 PCMD ext., Karachi 75270, Pakistan.
H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Pakistan.
J Mol Struct. 2022 Feb 15;1250:131920. doi: 10.1016/j.molstruc.2021.131920. Epub 2021 Nov 19.
A new coronavirus strain called as SARS-CoV-2 has emerged from Wuhan, China in late 2019 and it caused a worldwide pandemic in a few months. After the Second World War, it is the biggest calamity observed as there is no specific US Food and Drugs Administration (USFDA) approved drug or vaccine available globally for the treatment. Several clinical trials are ongoing for therapeutic alternatives, however with little success rate. Considering that the time is crucial, the drug repurposing and data obtained from models are one of the most important approaches to identify possible lead inhibitors against SARS-CoV-2. More recently, the Direct Acting Antivirals (DAAs) are emerged as the most promising drugs to control viral infection. The Main Protease (Mpro), a key enzyme in the SARS-CoV-2 replication cycle, is found close homolog to the Hepatitis C Virus (HCV) protease and could be susceptible of blocking its activity by DAAs. In the current study, the DAAs were investigated as antivirals using structure based computational approach against Mpro of SARS-CoV-2 to propose them as new therapeutics. In total, 20 DAAs of HCV, including a reference compound O6K were docked against Mpro. The docked structures were examined and resulted in the identification of six highly promising DAAs i.e. beclabuvir, elbasvir, paritaprevir, grazoprevir, simeprevir, and asunapevir exhibiting high theoretical binding affinity to Mpro from SARS-CoV-2 in comparison to other DAAs. Furthermore, the post docking analysis revealed that Cys145, Glu166, His163, Thr26, His41, and Met165 played potential role for the binding of these DAAs inside binding site of Mpro. Furthermore, the correlation between binding energies were found in accord with the results from the reported ICs for some DAAs. Overall, the current study provides insight to combat COVID-19 using FDA-approved DAAs as repurposed drugs.
一种名为严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的新型冠状病毒于2019年末在中国武汉出现，并在几个月内引发了全球大流行。第二次世界大战之后，这是所观察到的最大灾难，因为全球没有美国食品药品监督管理局（USFDA）批准的用于治疗的特定药物或疫苗。目前正在进行多项针对治疗替代方案的临床试验，但成功率很低。考虑到时间至关重要，药物重新利用以及从模型中获得的数据是识别针对SARS-CoV-2的可能先导抑制剂的最重要方法之一。最近，直接作用抗病毒药物（DAA）已成为控制病毒感染最有前景的药物。主要蛋白酶（Mpro）是SARS-CoV-2复制周期中的关键酶，被发现与丙型肝炎病毒（HCV）蛋白酶高度同源，并且可能会被DAA抑制其活性。在本研究中，使用基于结构的计算方法针对SARS-CoV-2的Mpro研究了DAA作为抗病毒药物，以将它们作为新的治疗方法提出。总共将20种HCV的DAA，包括一种参考化合物O6K，与Mpro进行对接。对对接结构进行了检查，结果鉴定出六种非常有前景的DAA，即比克瑞韦、艾尔巴韦、帕利瑞韦、格卡瑞韦、simeprevir和阿舒瑞韦，与其他DAA相比，它们对来自SARS-CoV-2的Mpro表现出高理论结合亲和力。此外，对接后分析表明，半胱氨酸145、谷氨酸166、组氨酸163、苏氨酸26、组氨酸41和甲硫氨酸165在这些DAA与Mpro结合位点内的结合中发挥了潜在作用。此外，发现结合能之间的相关性与一些DAA报道的IC结果一致。总体而言，本研究为使用FDA批准的DAA作为重新利用的药物对抗2019冠状病毒病提供了思路。
