In silico identification of widely used and well-tolerated drugs as potential SARS-CoV-2 3C-like protease and viral RNA-dependent RNA polymerase inhibitors for direct use in clinical trials

Abstract

Despite strict measures taken by many countries, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be an issue of global concern. Currently, there are no clinically proven pharmacotherapies for coronavirus disease 2019, despite promising initial results obtained from drugs such as azithromycin and hydroxychloroquine. Therefore, the repurposing of clinically approved drugs for use against SARS-CoV-2 has become a viable strategy. Here, we searched for drugs that target SARS-CoV-2 3C-like protease (3CL pro) and viral RNA-dependent RNA polymerase (RdRp) by in silico screening of the U.S. Food and Drug Administration approved drug library. Well-tolerated and widely used drugs were selected for molecular dynamics (MD) simulations to evaluate drug-protein interactions and their persistence under physiological conditions. Tetracycline, dihydroergotamine, ergotamine, dutasteride, nelfinavir, and paliperidone formed stable interactions with 3CL pro based on MD simulation results. Similar analysis with RdRp showed that eltrombopag, tipranavir, ergotamine, and conivaptan bound to the enzyme with high binding free energies. Docking results suggest that ergotamine, dihydroergotamine, bromocriptine, dutasteride, conivaptan, paliperidone, and tipranavir can bind to both enzymes with high affinity. As these drugs are well tolerated, cost-effective, and widely used, our study suggests that they could potentially to be used in clinical trials for the treatment of SARS-CoV-2infected patients.

Simeprevir and Eltrombopag as Potential Inhibitors of SARS-CoV2 Proteases: A Molecular Docking and Virtual Screening Approach to Combat COVID-19

“…Eltrombopag, an FDA approved drug used to treat low blood platelet count showed strongest binding affinity to PLpro enzyme suggesting potential inhibitor of the enzyme. Similar to the present finding, Gul et al (2020) also reported strong binding affinity of eltrombopag with 3CLpro and RdRp enzyme. Like many other studies, we also found strong binding affinity of ivermectin, an antihelmintic drug, with both the protease enzymes of SARS-CoV and -CoV-2.…”

Identification of Potent and Safe Antiviral Therapeutic Candidates Against SARS-CoV-2

“…This screening confirms previous reports demonstrating anti-SARS-CoV-2 activity of hydroxychloroquine, amlodipine besylate, arbidol hydrochloride, tilorone 2HCl, dronedarone hydrochloride, mefloquine, celecoxib, and thioridazine hydrochloride (8)(9)(10)(25)(26)(27), while identifying additional 12 drugs. However, there are seven drugs have been reported when our manuscript was underreview (28)(29)(30)(31)(32)(33)(34)(35)(36)(37). The underlying mechanisms of viral replication inhibition by these drugs are not clear.…”

Repurposed application of doxycycline in COVID 19 treatment

“…29 In addition, severe acute respiratory syndrome-related coronavirus (SARS-CoV) encompasses a papain-like protease that significantly triggers an early growth response protein 1 (Egr-1)-dependent activation of transforming growth factor beta 1 (TGF-β 1), resulting in up-regulation of pro-fibrotic responses in vitro and in vivo in the lungs. [30][31] Recent computational methods study identified doxycycline among the drugs that could potentially be used to inhibit SARS-CoV-2 papain-like protease. 30,31…”

“…[30][31] Recent computational methods study identified doxycycline among the drugs that could potentially be used to inhibit SARS-CoV-2 papain-like protease. 30,31…”