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Cited by 255Computational Drug Discovery MethodsSARS-CoV-2 and COVID-19 ResearchCholinesterase and Neurodegenerative Diseases

Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs

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Li, Zhe, Li, Xin, Huang, Yi-You, Wu, Yaoxing, Liu, Runduo, Zhou, Lingli, Lin, Yuxi, Wu, Deyan +9 more·2020·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2010470117PMC PMC7959488

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Abstract

Significance: Drug repurposing effort for treatment of a new disease, such as COVID-19, usually starts from a virtual screening of existing drugs, followed by experimental validation, but the actual hit rate is generally rather low with traditional computational methods. It has been demonstrated that a new virtual screening approach with accelerated free energy perturbation-based absolute binding free energy (FEP-ABFE) predictions can reach an unprecedentedly high hit rate, leading to successful identification of 15 potent inhibitors of SARS-CoV-2 main protease (M pro ) from 25 computationally selected drugs under a threshold of K i = 4 μM. The outcomes of this study are valuable for not only drug repurposing to treat COVID-19 but also demonstrating the promising potential of the FEP-ABFE prediction-based virtual screening approach.

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  • DIS is a potent SARS-CoV-2 main protease Mpro and PLpro inhibitor, also targets other SARS-CoV-2 proteins such as nsp13 and nsp14, and is an inhibitor of pyroptosis via inhibition of gasdermin D.

    “Recently, DIS was confirmed to be potent SARS-CoV-2 main proteases Mpro and PLpro inhibitor, but also targets other SARS-CoV-2 proteins such as nsp13 and nsp14 and is even an inhibitor of pyroptosis via inhibition of gasdermin D.93,94,95,96”

    From Off-label and repurposed use of disulfiram beyond alcohol dependence: A systematic review of clinical and preclinical evidence (2026) · cites this paper as [93]

    The Results and Discussion section (page not available) identifies disulfiram as a confirmed SARS-CoV-2 Mpro inhibitor and reports an IC50 of 4.7 µM in the authors’ test. The passages do not establish that it inhibits PLpro, targets nsp13 or nsp14, or inhibits pyroptosis through gasdermin D. The paper’s most potent Mpro inhibitor is DIP (dipyridamole), not DIS (disulfiram). (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Cited by

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Authors
Li, Z., Li, X., Huang, Y.-Y., Wu, Y., Liu, R., Zhou, L., Lin, Y., Wu, D., Zhang, L., Liu, H., Xu, X., Yu, K., Zhang, Y., Cui, J., Zhan, C.-G., Wang, X., & Luo, H.-B.
Affiliations
  • Sun Yat-sen University (CN)
  • Ocean University of China (CN)
  • Qingdao National Laboratory for Marine Science and Technology (CN)
  • Marine Biomedical Research Institute of Qingdao (CN)
  • Chinese Academy of Sciences (CN)
  • Guangzhou Women and Children Medical Center (CN)
  • University of Kentucky (US)
Corresponding author
  • Cui, Jun
  • Zhan, Chang-Guo
  • Wang, Xin
  • Luo, Hai-Bin
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2020-10-13
Volume
117
Issue
44
Pages
27381-27387
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2010470117
PMC
PMC7959488
OpenAlex
W3092297806
Cited by
255
References
1
Citations by year
2026: 13 · 2025: 13 · 2024: 24 · 2023: 32 · 2022: 58 · 2021: 89 · 2020: 26
FWCI
25.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Lanzhou University Institutional Repository (submittedVersion, cc-by-nc-sa)
  • Lanzhou University Institutional Repository (submittedVersion)
Funders
  • National Key R&D Program of China (2017YFB0202600)
  • National Natural Science Foundation of China (81903542, 81522041, 21877134)
  • Guangdong Provincial Key Laboratory of Construction Foundation (2017B030314030)
  • National Science Foundation (CHE-1111761)
Topics
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
Keywords
main protease, Mpro inhibitors, COVID-19 drug repurposing, hit rate, binding affinity prediction
MeSH terms
Betacoronavirus, COVID-19, SARS-CoV-2, Coronavirus 3C Proteases, Antiviral Agents, Chloroquine, Cysteine Endopeptidases, Dipyridamole, Humans, Hydroxychloroquine, Pneumonia, Viral, Protease Inhibitors, Molecular Structure, Viral Nonstructural Proteins, Coronavirus Infections, Drug Repositioning, Pandemics, Molecular Docking Simulation

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