计算筛选抗SARS-Cov-2主要蛋白酶（Mpro）的药物和天然产物作为潜在的COVID-19治疗药物
Computational screening of repurposed drugs and natural products against SARS-Cov-2 main protease (Mpro) as potential COVID-19 therapies
摘要：
仍然迫切需要确定可能适合治疗COVID-19感染患者的现有药物。药物很少作用于单个分子靶点，脱靶效应通常导致不良副作用，有时还导致特定疾病靶点之间的有益协同作用。在某些情况下，偏离目标的活动也导致了重磅炸弹药物的出现，例如治疗勃起功能障碍的伟哥和治疗男性脱发的米诺地尔。已经在使用或在临床试验中的药物加上已批准的天然产物构成了发现治疗药物的丰富资源，这些药物可以重新用于现有和新的疾病，因为它们已经被评估了人体安全性。因此，一个关键问题是如何快速有效地筛选这些化合物对新的流行性病原体（如COVID-19）的活性。在这里，我们展示了如何使用快速和强大的计算过程来筛选大型药物和天然化合物库，以确定那些可能抑制SARS-Cov-2（3CL pro，Mpro）的主要蛋白酶。我们展示了所得到的具有最强结合亲和力的候选物的短名单如何高度富集已被独立鉴定为抗COVID-19的潜在抗病毒药物的化合物。最佳候选药物还包括大量先前未被确定为具有潜在COVID-19活性的药物和天然产物，从而为实验验证提供了额外的目标。这种计算机筛选管道也可能有助于重新利用现有药物和发现针对其他医学重要病原体的新候选药物，并用于未来的大流行病。
英文摘要：
There remains an urgent need to identify existing drugs that might be suitable for treating patients suffering from COVID-19 infection. Drugs rarely act at a single molecular target, with off target effects often being responsible for undesirable side effects and sometimes, beneficial synergy between targets for a specific illness. Off target activities have also led to blockbuster drugs in some cases, e.g. Viagra for erectile dysfunction and Minoxidil for male pattern hair loss. Drugs already in use or in clinical trials plus approved natural products constitute a rich resource for discovery of therapeutic agents that can be repurposed for existing and new conditions, based on the rationale that they have already been assessed for safety in man. A key question then is how to rapidly and efficiently screen such compounds for activity against new pandemic pathogens such as COVID-19. Here we show how a fast and robust computational process can be used to screen large libraries of drugs and natural compounds to identify those that may inhibit the main protease of SARS-Cov-2 (3CL pro, Mpro). We show how the resulting shortlist of candidates with strongest binding affinities is highly enriched in compounds that have been independently identified as potential antivirals against COVID-19. The top candidates also include a substantial number of drugs and natural products not previously identified as having potential COVID-19 activity, thereby providing additional targets for experimental validation. This in silico screening pipeline may also be useful for repurposing of existing drugs and discovery of new drug candidates against other medically important pathogens and for use in future pandemics.
机构、总结、中文摘要均由AI分析而来，可能存在错误，请以论文正文为准。
