Structural stability of SARS-CoV-2 3CLpro and identification of quercetin as an inhibitor by experimental screening
Structural stability of SARS-CoV-2 3CLpro and identification of quercetin as an inhibitor by experimental screening
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DOI：
10.1016/j.ijbiomac.2020.07.235
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发表时间：
2020-12-01
影响因子：
8.2
通讯作者：
Velazquez-Campoy, Adrian
中科院分区：
文献类型：
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作者：
Abian, Olga;Ortega-Alarcon, David;Velazquez-Campoy, Adrian
2019冠状病毒病（COVID-19）引发的全球卫生紧急情况促使人们寻找其病原体严重急性呼吸道综合征冠状病毒2（SARS-CoV-2）的预防和治疗方法。有许多潜在的药物发现和开发靶点来治疗这种疾病。这些靶标之一是主要蛋白酶Mpro或3CLpro，其在冠状病毒中高度保守。3CLpro是病毒复制周期中的重要参与者，处理大型病毒多聚蛋白并使单个蛋白质发挥功能。我们报告的生物物理特性的结构稳定性和催化活性的3CLpro从SARS-CoV-2，从一个合适的实验在体外分子筛选程序已被设计。通过筛选由约150种化合物组成的小化学库，天然产物槲皮素被鉴定为相当有效的SARS-CoV-2 3CLpro抑制剂（Ki类似于7 μ M）。槲皮素可以显示与3CLpro使用生物物理技术和结合的活性位点的分子模拟。槲皮素具有众所周知的药代动力学和ADMET特性，可被视为进一步优化和开发的良好候选药物，或重新定位用于COVID-19治疗。(C)2020爱思唯尔B. V.保留所有权利。
The global health emergency generated by coronavirus disease 2019 (COVID-19) has prompted the search for preventive and therapeutic treatments for its pathogen, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There are many potential targets for drug discovery and development to tackle this disease. One of these targets is the main protease, Mpro or 3CLpro, which is highly conserved among coronaviruses. 3CLpro is an essential player in the viral replication cycle, processing the large viral polyproteins and rendering the individual proteins functional. We report a biophysical characterization of the structural stability and the catalytic activity of 3CLpro from SARS-CoV-2, from which a suitable experimental in vitro molecular screening procedure has been designed. By screening of a small chemical library consisting of about 150 compounds, the natural product quercetin was identified as reasonably potent inhibitor of SARS-CoV-2 3CLpro (K-i similar to 7 mu M). Quercetin could be shown to interact with 3CLpro using biophysical techniques and bind to the active site in molecular simulations. Quercetin, with well-known pharmacokinetic and ADMET properties, can be considered as a good candidate for further optimization and development, or repositioned for COVID-19 therapeutic treatment. (C) 2020 Elsevier B.V. All rights reserved.