Introduction. The emergence of SARS-CoV-2 has taken humanity off guard. Following an outbreak of SARS-CoV in 2002, and MERS-CoV about 10 years later, SARS-CoV-2 is the third coronavirus in less than 20 years to cross the species barrier and start spreading by human-to-human transmission. It is the most infectious of the three, currently causing the COVID-19 pandemic. No treatment has been approved for COVID-19. We previously proposed targets that can serve as binding sites for antiviral drugs for multiple coronaviruses, and here we set out to find current drugs that can be repurposed as COVID-19 therapeutics.Aim. To identify drugs against COVID-19, we performed an in silico virtual screen with the US Food and Drug Administration (FDA)-approved drugs targeting the RNA-dependent RNA polymerase (RdRP), a critical enzyme for coronavirus replication.Methodology. Initially, no RdRP structure of SARS-CoV-2 was available. We performed basic sequence and structural analysis to determine if RdRP from SARS-CoV was a suitable replacement. We performed molecular dynamics simulations to generate multiple starting conformations that were used for the in silico virtual screen. During this work, a structure of RdRP from SARS-CoV-2 became available and was also included in the in silico virtual screen.Results. The virtual screen identified several drugs predicted to bind in the conserved RNA tunnel of RdRP, where many of the proposed targets were located. Among these candidates, quinupristin is particularly interesting because it is expected to bind across the RNA tunnel, blocking access from both sides and suggesting that it has the potential to arrest viral replication by preventing viral RNA synthesis. Quinupristin is an antibiotic that has been in clinical use for two decades and is known to cause relatively minor side effects.Conclusion. Quinupristin represents a potential anti-SARS-CoV-2 therapeutic. At present, we have no evidence that this drug is effective against SARS-CoV-2 but expect that the biomedical community will expeditiously follow up on our in silico findings.

中文翻译：

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潜在的 RNA 依赖性 RNA 聚合酶抑制剂作为对抗 SARS-CoV-2 的前瞻性疗法。


介绍。 SARS-CoV-2的出现让人类措手不及。继 2002 年爆发 SARS-CoV 和大约 10 年后爆发 MERS-CoV 后，SARS-CoV-2 是不到 20 年内第三种跨越物种屏障并开始通过人际传播传播的冠状病毒。它是三种病毒中传染性最强的，目前导致了 COVID-19 大流行。尚未批准针对 COVID-19 的治疗方法。我们之前提出了可以作为多种冠状病毒抗病毒药物结合位点的靶点，在这里我们着手寻找可以重新用作 COVID-19 疗法的现有药物。为了识别针对 COVID-19 的药物，我们对美国食品和药物管理局 (FDA) 批准的针对 RNA 依赖性 RNA 聚合酶 (RdRP) 的药物进行了计算机虚拟筛选，RdRP 是冠状病毒复制的关键酶。最初，没有 SARS-CoV-2 的 RdRP 结构。我们进行了基本序列和结构分析，以确定来自 SARS-CoV 的 RdRP 是否是合适的替代品。我们进行了分子动力学模拟，以生成用于计算机虚拟屏幕的多个起始构象。在这项工作中，来自 SARS-CoV-2 的 RdRP 结构变得可用，并且也包含在计算机虚拟屏幕中。结果。虚拟筛选确定了几种预计会结合在 RdRP 保守 RNA 通道中的药物，其中许多提议的靶点都位于该通道中。在这些候选药物中，奎努普丁特别令人感兴趣，因为它预计会跨过 RNA 隧道结合，阻断两侧的进入，并表明它有可能通过阻止病毒 RNA 合成来阻止病毒复制。 奎奴普丁是一种抗生素，已在临床使用二十年，已知其副作用相对较小。结论。奎奴普丁是一种潜在的抗 SARS-CoV-2 治疗药物。目前，我们没有证据表明该药物对 SARS-CoV-2 有效，但预计生物医学界将迅速跟进我们的计算机研究结果。