Identification of Atovaquone, Ouabain and Mebendazole as FDA Approved Drugs Tar-geting SARS-CoV-2 (Version 4)

Abstract

<p>The newly emerged coronavirus, SARS-CoV-2, and the resulting COVID-19 disease, has spread swiftly across the globe since its initial detection in December 2019. Given the heavy toll of this pandemic, therapeutic options for treatment are urgently needed. Here, we adopted a repositioning approach using in-silico molecular modeling to screen FDA-approved drugs with established safety profiles for potential inhibitory effects against SARS-CoV-2. We used structure-based drug design to screen more than 2000 FDA approved drugs against SARS-CoV-2 main protease enzyme (Mpro) substrate-binding pocket, focusing on two potential sites (central and terminal sites) to identify hits based on their binding energies, binding modes, interacting amino acids, and therapeutic indications. We additionally screened the top hits from both sites for potential covalent binding via nucleophilic thiol attack of Cys 145. High-scoring candidates were then screened for antiviral activity against infectious SARS-CoV-2 in a cell-based viral replication assay, and counterscreened for toxicity. Atovaquone, Mebendazole, and Ouabain exhibited antiviral efficacy with IC50s well within their respective therapeutic plasma concentrations (low nanomolar to low micromolar range), and limited toxic effects. Notably, all three were predicted in docking studies to covalently bind SARS-CoV-2 Mpro, underscoring the utility of this in-silico approach for identifying putative antivirals for repurposing. These results do not confirm efficacy in animal models or in humans, but rather serve as a starting point for testing the antiviral potential of select FDA-approved drugs, either individually or in combination.<br></p>

Association between statin use and outcomes in patients with coronavirus disease 2019 (COVID-19): a nationwide cohort study

“… 2 Although the data may be biased by patient selection, treatment indication and residual confounding, including lack of adjustment for socioeconomic status and prehospital medication, this controversial finding merits further investigation. In addition, Farag et al 3 performed a computer-based study and used a structure-based drug design to screen more than 2000 Food and Drug Administration-approved drugs against SARS-CoV-2 main protease enzyme substrate-binding pocket. Other than antiviral drugs, the authors also identified rosuvastatin as a drug that may be useful against SARS-CoV-2.…”

Histamine receptors and COVID-19

“…Studies have also reported that other potential mast cell mediator release and function-modifying drugs could interact with important pathways in viral replication. In silico docking studies have indicated that the cysteinyl leukotriene (cysLT) receptor antagonist montelukast that is indicated for the treatment of asthma [5,44], the 5-lipoxygenase (5-LOX) inhibitor setileuton [45] and the H 1 receptor antagonists fexofenadine [44], mizolastine and cetirizine [46] interact with M pro , whereas the mast cell stabiliser cromolyn is a potential RdRP inhibitor [5]. Another work highlighted the interaction of montelukast with PL pro [6].…”

Pharmacoinformatics and molecular dynamics simulation studies reveal potential covalent and FDA-approved inhibitors of SARS-CoV-2 main protease 3CLpro

“…Structure-based activity studies and various highthroughput studies have identified distinct inhibitors of SARS-CoV and MERS-CoV main proteases (Anand et al, 2003;Bacha et al, 2004;Kumar et al, 2017;Ryu et al, 2010). Therefore, it is crucial to identify novel inhibitors of SARS-CoV-2 main protease to control COVID-19 (Farag et al, 2020;Haider et al, 2020;Wang, 2020). On the other hand, main protease is highly conserved across coronaviruses.…”