[논문]Drugs repurposed for COVID-19 by virtual screening of 6,218 drugs and cell-based assay

Jang, Woo Dae; Jeon, Sangeun; Kim, Seungtaek; Lee, Sang Yup

doi:10.1073/pnas.2024302118

[해외논문] Drugs repurposed for COVID-19 by virtual screening of 6,218 drugs and cell-based assay 원문보기

Proceedings of the National Academy of Sciences of the United States of America, v.118 no.30, 2021년, pp.e2024302118 - e2024302118

Jang, Woo Dae (Metabolic and Biomolecular Engineering National Research Laboratory, Department of Chemical and Biomolecular Engineering (BK21 four), KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea) , Jeon, Sangeun , Kim, Seungtaek (Zoonotic Virus Laboratory, Institut Pasteur Korea, Seongnam 13488, Republic of Korea) , Lee, Sang Yup

Abstract ▼ AI-Helper

SignificanceRecent spread of SARS-CoV-2 has sparked significant health concerns of emerging infectious viruses. Drug repurposing is a tangible strategy for developing antiviral agents within a short period. In general, drug repurposing starts with virtual screening of approved drugs employing docking simulations. However, the actual hit rate is low, and most of the predicted compounds are false positives. To tackle the challenges, we report advanced virtual screening with pre- and postdocking pharmacophore filtering of 6,218 drugs for COVID-19. Notably, 7 out of 38 compounds showed efficacies in inhibiting SARS-CoV-2 in Vero cells. Three of these were also found to inhibit SARS-CoV-2 in human Calu-3 cells. Furthermore, three drug combinations showed strong synergistic effects in SARS-CoV-2 inhibition at their clinically achievable concentrations.The COVID-19 pandemic caused by SARS-CoV-2 is an unprecedentedly significant health threat, prompting the need for rapidly developing antiviral drugs for the treatment. Drug repurposing is currently one of the most tangible options for rapidly developing drugs for emerging and reemerging viruses. In general, drug repurposing starts with virtual screening of approved drugs employing various computational methods. However, the actual hit rate of virtual screening is very low, and most of the predicted compounds are false positives. Here, we developed a strategy for virtual screening with much reduced false positives through incorporating predocking filtering based on shape similarity and postdocking filtering based on interaction similarity. We applied this advanced virtual screening approach to repurpose 6,218 approved and clinical trial drugs for COVID-19. All 6,218 compounds were screened against main protease and RNA-dependent RNA polymerase of SARS-CoV-2, resulting in 15 and 23 potential repurposed drugs, respectively. Among them, seven compounds can inhibit SARS-CoV-2 replication in Vero cells. Three of these drugs, emodin, omipalisib, and tipifarnib, show anti-SARS-CoV-2 activities in human lung cells, Calu-3. Notably, the activity of omipalisib is 200-fold higher than that of remdesivir in Calu-3. Furthermore, three drug combinations, omipalisib/remdesivir, tipifarnib/omipalisib, and tipifarnib/remdesivir, show strong synergistic effects in inhibiting SARS-CoV-2. Such drug combination therapy improves antiviral efficacy in SARS-CoV-2 infection and reduces the risk of each drug’s toxicity. The drug repurposing strategy reported here will be useful for rapidly developing drugs for treating COVID-19 and other viruses.

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