A novel method of virtual screening to look for existing drugs which have the potential to inhibit the SARS-CoV-2 protease Mpro identifies dipyridamole as the best candidate.

Key Messages

Mpro is the main protease (enzyme) that is a key protein required for the replication of the SARS-CoV-2 virus. For this reason, Mpro is an attractive drug target for COVID-19 treatment.

A new drug-repurposing approach, using a novel computer modeling method called “accelerated free energy perturbation-based virtual screening” tested existing drugs for their potential to inhibit the Mpro protein.

Out of 25 computationally selected drugs, 15 were identified as strong potential inhibitors of Mpro, and of these, the strongest potential drug identified was dipyridamole.

Proceedings of the National Academy of Sciences

Publication Date: November 3, 2020
Peer Reviewed: Yes
Publication Type: Original | Preclinical
DOI: https://www.doi.org/10.1073/pnas.2010470117

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


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.