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

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

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 (M(pro)). 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 M(pro). The most potent one is dipyridamole (inhibitory constant K(i) = 0.04 µM) which has shown promising therapeutic effects in subsequently conducted clinical studies for treatment of patients with COVID-19. Additionally, hydroxychloroquine (K(i) = 0.36 µM) and chloroquine (K(i) = 0.56 µM) were also found to potently inhibit SARS-CoV-2 M(pro). We anticipate that the FEP-ABFE prediction-based virtual screening approach will be useful in many other drug repurposing or discovery efforts.