Zia Komal, Khan Salman Ali, Ashraf Sajda, Nur-E-Alam Mohammad, Ahmed Sarfaraz, Ul-Haq Zaheer
Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box. 2457, Riyadh 11451, Kingdom of Saudi Arabia.
J Mol Struct. 2021 May 5;1231:129953. doi: 10.1016/j.molstruc.2021.129953. Epub 2021 Jan 19.
The pandemic of COVID-19 has an unprecedented impact on global health and economy. The novel SARS-CoV-2 is recognized as the etiological agent of current outbreak. Because of its contagious human-to-human transmission, it is an utmost global health emergency at present. To mitigate this threat many scientists and researchers are racing to develop antiviral therapy against the virus. Unfortunately, to date no vaccine or antiviral therapeutic is approved thus there is an urgent need to discover antiviral agent to help the individual who are at high risk. Virus main protease or chymotrypsin-like protease plays a pivotal role in virus replication and transcription; thus, it is considered as an attractive drug target to combat the COVID-19. In this study, multistep structure based virtual screening of CAS antiviral database is performed for the identification of potent and effective small molecule inhibitors against chymotrypsin-like protease of SARS-CoV-2. Consensus scoring strategy combine with flexible docking is used to extract potential hits. As a result of extensive virtual screening, 4 hits were shortlisted for MD simulation to study their stability and dynamic behavior. Insight binding modes demonstrated that the selected hits stabilized inside the binding pocket of the target protein and exhibit complementarity with the active site residues. Our study provides compounds for further in vitro and in vivo studies against SARS-CoV-2.
新型冠状病毒肺炎大流行对全球健康和经济产生了前所未有的影响。新型严重急性呼吸综合征冠状病毒2被认为是当前疫情的病原体。由于其在人际间具有传染性，它目前是极其严重的全球卫生紧急事件。为了减轻这一威胁，许多科学家和研究人员正在竞相研发针对该病毒的抗病毒疗法。不幸的是，迄今为止尚无疫苗或抗病毒治疗药物获批，因此迫切需要发现抗病毒药物来帮助高危人群。病毒主要蛋白酶或类胰凝乳蛋白酶在病毒复制和转录中起关键作用；因此，它被认为是对抗新型冠状病毒肺炎的一个有吸引力的药物靶点。在本研究中，对化学文摘社抗病毒数据库进行了基于多步结构的虚拟筛选，以鉴定针对严重急性呼吸综合征冠状病毒2类胰凝乳蛋白酶的有效小分子抑制剂。结合柔性对接的共识评分策略用于筛选潜在的活性化合物。经过广泛的虚拟筛选，4种活性化合物被入围进行分子动力学模拟，以研究它们的稳定性和动态行为。深入的结合模式表明，所选活性化合物稳定在靶蛋白的结合口袋内，并与活性位点残基具有互补性。我们的研究为进一步开展针对严重急性呼吸综合征冠状病毒2的体外和体内研究提供了化合物。
