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 pK_a 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.

中文翻译：

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虚拟和体外抗病毒筛查使新冠肺炎 (COVID-19) 治疗药物重获新生

治愈早期 COVID-19 感染患者的迫切需要迫切需要药物重新定位策略，能够通过融合计算、实验和药代动力学专业知识来有效地识别新的、可靠的治疗方法。在这里，我们报告了通过虚拟和实验筛选策略相结合并从已批准的药物中筛选出来的新的潜在 COVID-19 疗法。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，根据近 4000 种已批准药物的库筛选结构相似性。根据与 HCQ 的结构相似性，选择排名靠前的药物进行体外抗病毒评估。在选定的药物中，珠氯哌噻吨和奈必洛尔均能有效阻断 SARS-CoV-2 感染，EC ₅₀值在低微摩尔范围内，经独立实验证实。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）的抗 SARS-CoV-2 潜力。在试图了解“羟氯喹”的作用机制时，p K _a和 HCQ 芳香核心都可能发挥作用。此外，我们还发现阿莫地喹代谢物以及较小程度的珠氯哌噻吨和奈比洛尔在 SARS-CoV-2 滴度降低测定中具有活性。考虑到提高疗效和安全性的需要，我们建议珠氯哌噻醇、奈必洛尔和阿莫地喹作为针对 SARS-CoV-2 感染早期阶段临床试验的潜在候选药物，并讨论它们作为当前佐剂（即瑞德西韦和阿莫地喹）的潜在用途。法匹拉韦）COVID-19 疗法。