Computational Selectivity Assessment of Protease Inhibitors against SARS-CoV-2.
Computational Selectivity Assessment of Protease Inhibitors against SARS-CoV-2.
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DOI：
10.3390/ijms22042065
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发表时间：
2021-02-19
影响因子：
5.6
通讯作者：
Smieško M
中科院分区：
文献类型：
--
作者：
Fischer A;Sellner M;Mitusińska K;Bzówka M;Lill MA;Góra A;Smieško M
严重急性呼吸道综合征冠状病毒2型（SARS-CoV-2）的大流行对全球健康构成严重威胁。由于没有特定的治疗方法，世界各地的研究人员筛选化合物来抑制SARS-CoV-2的各种分子靶标，包括病毒复制所必需的主要蛋白酶（Mpro）。由于这些发现工作的高度紧迫性，脱靶结合，这是药物诱导的毒性和安全性相关的药物损耗的主要原因之一，被忽视。在这里，我们使用分子对接，毒性分析，和多分子动力学（MD）协议，以评估33个非共价抑制剂的SARS-CoV-2 Mpro对8个蛋白酶和16个抗靶点的选择性。蛋白酶组包括SARS-CoV Mpro、组织蛋白酶G、半胱天冬酶-3、泛素羧基末端水解酶L1（UCHL 1）、凝血酶、因子Xa、糜酶和前列腺素。几种评估的化合物对蛋白酶组以及选定的抗靶标表现出相当大的脱靶结合。我们的研究结果进一步表明与糜酶和组织蛋白酶G脱靶结合的风险很高。因此，在未来的发现项目中，实验选择性评估应针对这些蛋白酶。正如我们报告的那样，以前没有进行过SARS-CoV-2 Mpro抑制剂的系统选择性评估。
The pandemic of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious global health threat. Since no specific therapeutics are available, researchers around the world screened compounds to inhibit various molecular targets of SARS-CoV-2 including its main protease (Mpro) essential for viral replication. Due to the high urgency of these discovery efforts, off-target binding, which is one of the major reasons for drug-induced toxicity and safety-related drug attrition, was neglected. Here, we used molecular docking, toxicity profiling, and multiple molecular dynamics (MD) protocols to assess the selectivity of 33 reported non-covalent inhibitors of SARS-CoV-2 Mpro against eight proteases and 16 anti-targets. The panel of proteases included SARS-CoV Mpro, cathepsin G, caspase-3, ubiquitin carboxy-terminal hydrolase L1 (UCHL1), thrombin, factor Xa, chymase, and prostasin. Several of the assessed compounds presented considerable off-target binding towards the panel of proteases, as well as the selected anti-targets. Our results further suggest a high risk of off-target binding to chymase and cathepsin G. Thus, in future discovery projects, experimental selectivity assessment should be directed toward these proteases. A systematic selectivity assessment of SARS-CoV-2 Mpro inhibitors, as we report it, was not previously conducted.
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DOI：
10.1016/j.ijantimicag.2020.106055
发表时间：
2020-08-01
影响因子：
10.8
作者：
He, Jun;Hu, Lijun;Ye, Wencai
通讯作者：
Ye, Wencai
影响因子：
6.1
作者：
Kandeel, Mahmoud;Al-Nazawi, Mohammed
通讯作者：
Al-Nazawi, Mohammed
影响因子：
56.9
作者：
Dai, Wenhao;Zhang, Bing;Liu, Hong
通讯作者：
Liu, Hong
影响因子：
7.3
作者：
Ghanakota, Phani;Carlson, Heather A.
通讯作者：
Carlson, Heather A.
影响因子：
7.3
作者：
Halgren, TA;Murphy, RB;Banks, JL
通讯作者：
Banks, JL