Free energy perturbation–based large-scale virtual screening for effective drug discovery against COVID-19

As a theoretically rigorous and accurate method, FEP-ABFE (Free Energy Perturbation-Absolute Binding Free Energy) calculations showed great potential in drug discovery, but its practical application was difficult due to high computational cost. To rapidly discover antiviral drugs targeting SARS-CoV-2 Mpro and TMPRSS2, we performed FEP-ABFE–based virtual screening for ∼12,000 protein-ligand binding systems on a new generation of Tianhe supercomputer. A task management tool was specifically developed for automating the whole process involving more than 500,000 MD tasks. In further experimental validation, 50 out of 98 tested compounds showed significant inhibitory activity towards Mpro, and one representative inhibitor, dipyridamole, showed remarkable outcomes in subsequent clinical trials. This work not only demonstrates the potential of FEP-ABFE in drug discovery but also provides an excellent starting point for further development of anti-SARS-CoV-2 drugs. Besides, ∼500 TB of data generated in this work will also accelerate the further development of FEP-related methods.

Therapeutic targets and potential agents for the treatment of COVID-19.

The outbreak of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has become a global crisis. As of November 9, COVID-19 has already spread to more than 190 countries with 50,000,000 infections and 1,250,000 deaths. Effective therapeutics and drugs are in high demand. The structure of SARS-CoV-2 is highly conserved with those of SARS-CoV and Middle East respiratory syndrome-CoV. Enzymes, including RdRp, Mpro /3CLpro , and PLpro , which play important roles in viral transcription and replication, have been regarded as key targets for therapies against coronaviruses, including SARS-CoV-2. The identification of readily available drugs for repositioning in COVID-19 therapy is a relatively rapid approach for clinical treatment, and a series of approved or candidate drugs have been proven to be efficient against COVID-19 in preclinical or clinical studies. This review summarizes recent progress in the development of drugs against SARS-CoV-2 and the targets involved.

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

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.

Potential therapeutic effects of dipyridamole in the severely ill patients with COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause acute respiratory distress syndrome, hypercoagulability, hypertension, and multiorgan dysfunction. Effective antivirals with safe clinical profile are urgently needed to improve the overall prognosis. In an analysis of a randomly collected cohort of 124 patients with COVID-19, we found that hypercoagulability as indicated by elevated concentrations of D-dimers was associated with disease severity. By virtual screening of a U.S. FDA approved drug library, we identified an anticoagulation agent dipyridamole (DIP) in silico, which suppressed SARS-CoV-2 replication in vitro. In a proof-of-concept trial involving 31 patients with COVID-19, DIP supplementation was associated with significantly decreased concentrations of D-dimers (P < 0.05), increased lymphocyte and platelet recovery in the circulation, and markedly improved clinical outcomes in comparison to the control patients. In particular, all 8 of the DIP-treated severely ill patients showed remarkable improvement: 7 patients (87.5%) achieved clinical cure and were discharged from the hospitals while the remaining 1 patient (12.5%) was in clinical remission.