Virtual and In Vitro Antiviral Screening Revive Therapeutic Drugs for COVID-19.

The urgent need for a cure for early phase COVID-19 infected patients critically underlines drug repositioning strategies able to efficiently identify new and reliable treatments by merging computational, experimental, and pharmacokinetic expertise. Here we report new potential therapeutics for COVID-19 identified with a combined virtual and experimental screening strategy and selected among already approved drugs. We used hydroxychloroquine (HCQ), one of the most studied drugs in current clinical trials, as a reference template to screen for structural similarity against a library of almost 4000 approved drugs. The top-ranked drugs, based on structural similarity to HCQ, were selected for in vitro antiviral assessment. Among the selected drugs, both zuclopenthixol and nebivolol efficiently block SARS-CoV-2 infection with EC50 values in the low micromolar range, as confirmed by independent experiments. The anti-SARS-CoV-2 potential of ambroxol, amodiaquine, and its active metabolite (N-monodesethyl amodiaquine) is also discussed. In trying to understand the “hydroxychloroquine” mechanism of action, both pKa and the HCQ aromatic core may play a role. Further, we show that the amodiaquine metabolite and, to a lesser extent, zuclopenthixol and nebivolol are active in a SARS-CoV-2 titer reduction assay. Given the need for improved efficacy and safety, we propose zuclopenthixol, nebivolol, and amodiaquine as potential candidates for clinical trials against the early phase of the SARS-CoV-2 infection and discuss their potential use as adjuvant to the current (i.e., remdesivir and favipiravir) COVID-19 therapeutics.

对于早期新冠病毒感染患者治疗方法的迫切需求，凸显了药物再定位策略的重要性，这种策略通过融合计算、实验和药代动力学方面的专业知识，能够有效地确定新的可靠治疗方法。在此，我们报告了通过虚拟和实验相结合的筛选策略确定的针对新冠病毒的新的潜在治疗药物，这些药物是从已获批的药物中筛选出来的。我们使用羟氯喹（HCQ）——当前临床试验中研究最多的药物之一——作为参考模板，针对一个包含近4000种已获批药物的库进行结构相似性筛选。根据与羟氯喹的结构相似性，筛选出排名靠前的药物进行体外抗病毒评估。在所选药物中，珠氯噻醇和奈必洛尔都能有效阻断新冠病毒感染，半数有效浓度（EC50）值在低微摩尔范围内，这一点得到了独立实验的证实。还讨论了氨溴索、阿莫地喹及其活性代谢物（N - 单去乙基阿莫地喹）抗新冠病毒的潜力。在试图理解“羟氯喹”的作用机制时，pKa值和羟氯喹的芳香核心可能都起作用。此外，我们表明阿莫地喹代谢物，以及在较小程度上珠氯噻醇和奈必洛尔在新冠病毒滴度降低试验中具有活性。鉴于需要提高疗效和安全性，我们提出珠氯噻醇、奈必洛尔和阿莫地喹可作为针对新冠病毒感染早期阶段临床试验的潜在候选药物，并讨论了它们作为现有（如瑞德西韦和法匹拉韦）新冠病毒治疗药物辅助药物的潜在用途。