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.

https://www.pnas.org/content/pnas/117/44/27381.full.pdf

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

The pandemic caused by novel coronavirus disease 2019 (COVID-19) infecting millions of populations worldwide and counting, has demanded quick and potential therapeutic strategies. Current approved drugs or molecules under clinical trials can be a good pool for repurposing through in-silico techniques to quickly identify promising drug candidates. The structural information of recently released crystal structures of main protease (Mpro) in APO and complex with inhibitors, N3, and 13b molecules was utilized to explore the binding site architecture through Molecular dynamics (MD) simulations. The stable state of Mpro was used to conduct extensive virtual screening of the aforementioned drug pool. Considering the recent success of HIV protease molecules, we also used anti-protease molecules for drug repurposing purposes. The identified top hits were further evaluated through MD simulations followed by the binding free energy calculations using MM-GBSA. Interestingly, in our screening, several promising drugs stand out as potential inhibitors of Mpro. However, based on control (N3 and 13b), we have identified six potential molecules, Leupeptin Hemisulphate, Pepstatin A, Nelfinavir, Birinapant, Lypression and Octreotide which have shown the reasonably significant MM-GBSA score. Further insight shows that the molecules form stable interactions with hot-spot residues, that are mainly conserved and can be targeted for structure- and pharmacophore-based designing. The pharmacokinetic annotations and therapeutic importance have suggested that these molecules possess drug-like properties and pave their way for in-vitro studies.Communicated by Ramaswamy H. Sarma.

/pdf/identification-of-potential-molecules-against-covid-19-main-5cwaen9n82.pdf

Identification of Potential Molecules Against COVID-19 Main Protease Through Structure-Guided Virtual Screening Approach

At the time of writing this review, severe acute respiratory coronavirus syndrome-2 (SARS-CoV-2) has infected more than 2,355,853 patients and resulted in more than 164,656 deaths worldwide (as of 20 April 2020). This review highlights the preventive measures, available clinical therapies and the potential of vaccine development against SARS-CoV-2 by taking into consideration the strong genetic similarities of the 2003 epidemic SARS-CoV. Recent studies are investigating the repurposing of US FDA-approved drugs as there is no available vaccine yet with many attempts under clinical evaluation. Several antivirals, antimalarials and immunomodulators that have shown activity against SARS-CoV and Middle East coronavirus respiratory syndromes are being evaluated. In particular, hydroxychloroquine, remdesivir, favipiravir, arbidol, tocilizumab and bevacizumab have shown promising results. The main aim of this review is to provide an overview of this pandemic and where we currently stand.

/pdf/covid-19-pandemic-an-overview-of-epidemiology-pathogenesis-4owd4s3tyh.pdf

COVID-19 pandemic: an overview of epidemiology, pathogenesis, diagnostics and potential vaccines and therapeutics.

Lack of antiviral activity of darunavir against SARS-CoV-2.

Potential SARS-CoV-2 main protease inhibitors.

The new strain of Coronaviruses (SARS-CoV-2), and the resulting Covid-19 disease has spread swiftly across the globe after its initial detection in late December 2019 in Wuhan, China, resulting in a pandemic status declaration by WHO within 3 months Given the heavy toll of this pandemic, researchers are actively testing various strategies including new and repurposed drugs as well as vaccines In the current brief report, we adopted a repositioning approach using insilico molecular modeling screening using FDA approved drugs with established safety profiles for potential inhibitory effects on Covid-19 virus We started with structure based drug design by screening more than 2000 FDA approved drugs /against Covid-19 virus main protease enzyme (Mpro) substrate-binding pocket to identify potential hits based on their binding energies, binding modes, interacting amino acids, and therapeutic indications In addition, we elucidate preliminary pharmacophore features for candidates bound to Covid-19 virus Mpro substratebinding pocket The tohits include anti-viral drugs such as Darunavir, Nelfinavirand Saquinavir, some of which are already being tested in Covid-19 patients Interestingly, one of the most promising hits in our screen is the hypercholesterolemia drug Rosuvastatin These results certainly do not confirm or indicate antiviral activity, but can rather be used as a starting point for further in vitro and in vivo testing, either individually or in combination /div

Ayman, Farag, Ping, Wang, Mahmoud, Ahmed, Hesham, Sadek

Papers

Identification of FDA Approved Drugs Targeting COVID-19 Virus by Structure-Based Drug Repositioning