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LETTER REPLY TO MA AND WANG: Reliabilityofvariousinvitroactivityassayson SARS-CoV-2mainproteaseinhibitors Zhe Li a,1 , Yuxi Lin b,c,1, Yi-You Huang a,1, Runduo Liu a , Chang-Guo Zhan d,e,2 , Xin Wang b,f,2 , and Hai-Bin Luo a,g,2  Ma and Wang (1) tested our recently reported severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) main protease (M pro) noncovalent inhibitors (2) using their in vitro assays, and they obtained negligible or much lower inhibitory activities compared to ours. Notably,thefluorescence resonanceenergytransfer(FRET)-basedenzymaticassay used by Ma and Wang (1) is different from our FRETbased enzymatic assay in the M pro protein (discussed below) and the FRET substrate [longer than the more popularly used substrate (3, 4) utilized in our assay]. Ma and Wang (1) also used native mass spectrometry (MS) and thermal shift assays (TSA) to detect the protein-ligand binding. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]