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

Zhe Li, Xin Li, Yi You Huang, Yaoxing Wu, Runduo Liu, Lingli Zhou, Yuxi Lin, Deyan Wu, Lei Zhang, Hao Liu, Ximing Xu, Kunqian Yu, Yuxia Zhang, Jun Cui, Chang Guo Zhan, Xin Wang, Hai Bin Luo

Research output: Contribution to journalArticlepeer-review

166 Scopus citations


The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global crisis. There is no therapeutic treatment specific for COVID-19. It is highly desirable to identify potential antiviral agents against SARS-CoV-2 from existing drugs available for other diseases and thus repurpose them for treatment of COVID-19. In general, a 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. Here we report a virtual screening approach with accelerated free energy perturbation-based absolute binding free energy (FEP-ABFE) predictions and its use in identifying drugs targeting SARS-CoV-2 main protease (Mpro). The accurate FEP-ABFE predictions were based on the use of a restraint energy distribution (RED) function, making the practical FEP-ABFE−based virtual screening of the existing drug library possible. As a result, out of 25 drugs predicted, 15 were confirmed as potent inhibitors of SARS-CoV-2 Mpro. The most potent one is dipyridamole (inhibitory constant Ki = 0.04 μM) which has shown promising therapeutic effects in subsequently conducted clinical studies for treatment of patients with COVID-19. Additionally, hydroxychloroquine (Ki = 0.36 μM) and chloroquine (Ki = 0.56 μM) were also found to potently inhibit SARS-CoV-2 Mpro. We anticipate that the FEP-ABFE prediction-based virtual screening approach will be useful in many other drug repurposing or discovery efforts.

Original languageEnglish
Pages (from-to)27381-27387
Number of pages7
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number44
StatePublished - Nov 3 2020

Bibliographical note

Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.


  • Drug repurposing
  • Free energy perturbation
  • Main protease
  • SARS-CoV-2
  • Virtual screening

ASJC Scopus subject areas

  • General


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