In silico identification of widely used and well-tolerated drugs as potential SARS-CoV-2 3C-like protease and viral RNA-dependent RNA polymerase inhibitors for direct use in clinical trials
In silico identification of widely used and well-tolerated drugs as potential SARS-CoV-2 3C-like protease and viral RNA-dependent RNA polymerase inhibitors for direct use in clinical trials
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DOI：
10.1080/07391102.2020.1802346
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发表时间：
2020-08-04
影响因子：
4.4
通讯作者：
Kavakli, Ibrahim Halil
中科院分区：
文献类型：
--
作者：
Gul, Seref;Ozcan, Onur;Kavakli, Ibrahim Halil
尽管许多国家采取了严格措施，但严重急性呼吸系统综合征冠状病毒2 （SARS-CoV-2）仍然是全球关注的问题。目前，尽管阿奇霉素和羟氯喹等药物取得了令人鼓舞的初步结果，但还没有临床证实的2019冠状病毒病药物治疗方法。因此，重新利用临床批准的药物用于对抗SARS-CoV-2已成为一种可行的策略。在这里，我们通过计算机筛选美国食品和药物管理局批准的药物库，寻找针对SARS-CoV-2 3c样蛋白酶（3CL(pro)）和病毒RNA依赖性RNA聚合酶（RdRp）的药物。选择耐受性良好且应用广泛的药物进行分子动力学（MD）模拟，以评估药物-蛋白相互作用及其在生理条件下的持久性。MD模拟结果显示，四环素、二氢麦角胺、麦角胺、度他雄胺、奈非那韦和帕利哌酮与3CL（pro）形成稳定的相互作用。与RdRp相似的分析表明，依曲波巴、替普那韦、麦角胺和康尼伐坦以高结合自由能与酶结合。对接结果表明，麦角胺、二氢麦角胺、溴隐亭、度他雄胺、康尼伐坦、帕利哌酮和替普那韦都能与这两种酶高亲和力结合。由于这些药物耐受性良好，成本效益高，使用广泛，我们的研究表明，它们可能被用于治疗sars - cov -2感染患者的临床试验。由Ramaswamy H. Sarma传达
Despite strict measures taken by many countries, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be an issue of global concern. Currently, there are no clinically proven pharmacotherapies for coronavirus disease 2019, despite promising initial results obtained from drugs such as azithromycin and hydroxychloroquine. Therefore, the repurposing of clinically approved drugs for use against SARS-CoV-2 has become a viable strategy. Here, we searched for drugs that target SARS-CoV-2 3C-like protease (3CL(pro)) and viral RNA-dependent RNA polymerase (RdRp) by in silico screening of the U.S. Food and Drug Administration approved drug library. Well-tolerated and widely used drugs were selected for molecular dynamics (MD) simulations to evaluate drug-protein interactions and their persistence under physiological conditions. Tetracycline, dihydroergotamine, ergotamine, dutasteride, nelfinavir, and paliperidone formed stable interactions with 3CL(pro)based on MD simulation results. Similar analysis with RdRp showed that eltrombopag, tipranavir, ergotamine, and conivaptan bound to the enzyme with high binding free energies. Docking results suggest that ergotamine, dihydroergotamine, bromocriptine, dutasteride, conivaptan, paliperidone, and tipranavir can bind to both enzymes with high affinity. As these drugs are well tolerated, cost-effective, and widely used, our study suggests that they could potentially to be used in clinical trials for the treatment of SARS-CoV-2-infected patients. Communicated by Ramaswamy H. Sarma