PDF(Pubmed)
Abstract：
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.
摘要：
COVID-19的大流行对全球卫生和经济产生了前所未有的影响。新型SARS-CoV-2被认为是当前爆发的病原体。由于其传染性的人与人之间的传播，这是目前最严重的全球卫生紧急情况。为了减轻这种威胁，许多科学家和研究人员正在竞相开发针对该病毒的抗病毒疗法。不幸的是,迄今为止,没有疫苗或抗病毒治疗剂被批准,因此迫切需要发现抗病毒剂来帮助处于高风险的个体。病毒主要蛋白酶或胰凝乳蛋白酶样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COVID-19的一个有吸引力的药物靶标。在这项研究中,进行基于多步结构的CAS抗病毒数据库的虚拟筛选，以鉴定针对SARS-CoV-2的胰凝乳蛋白酶样蛋白酶的有效小分子抑制剂。共识评分策略与灵活对接相结合用于提取潜在命中。由于广泛的虚拟筛选，4次命中入围MD模拟，以研究其稳定性和动态行为。洞察力结合模式表明，选定的命中在靶蛋白的结合口袋内稳定，并表现出与活性位点残基的互补性。我们的研究为针对SARS-CoV-2的进一步体外和体内研究提供了化合物。
