<p></p><p>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 hydroxyquinoline. 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<sup>pro</sup>) 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<sup>pro</sup> 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-2-infected patients.</p><br><p></p>
A novel coronavirus (2019-nCoV), officially known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China. Despite drastic strict measures, the spread of this virus is ongoing all around the world. SARS-CoV-2 is an agent of coronavirus disease 2019 (COVID-19) characterized by pulmonary infection in humans. There is no vaccine developed against this virus and no approved medication to be used in a treatment yet. In this study, we performed in silico screening against two critical enzymes, 3C-like protease (3CL pro ) and viral RNA-dependent RNA polymerase (RdRp), which play important roles in the SARS-CoV-2 life cycle. During the screening, 3948 drugs approved by the U.S. Food and Drug Administration (FDA) to target the active site of 3CL pro and nsp8 binding sites of RdRp and, in turn, disturb SARS-CoV-2 life cycle in host cell. As a result, several drugs with high binding affinity to both SARS-Cov-2 3CL pro and RdRp targets were identified. While drugs such as tetracycline and its derivatives, dihydroergotamine, ergotamine, dutasteride, nelfinavir, paliperidone, and conivaptan were identified to bind SARS-Cov-2 3CL pro ; tipranavir, nelfinavir, dihydroergotamine, conivaptan, dutasterid and eltrombopag were found to bind nsp8 binding site of RdRp. Notably, further analysis of the results showed that ergotamine, dihydroergotamine, conivaptan, paliperidone, and tipranavir can bind to both enzymes with high affinity. Since these drugs are well tolerated, costeffective and widely used, our study suggested that tetracycline and its derivatives, dutasteride, ergotamine, bromocriptine, tipranavir, conivaptan, paliperidone, eltrombopag drugs have the potential to be used alone or in combination as adjuvant for the treatment of SARS-CoV-2 infected patients.
<p>Despite drastic strict measures, the spread of the SARS-CoV-2 is ongoing all around the world. There is no vaccine developed against this virus and no approved medication to be used for the treatment of COVID-2019. In this study, we performed <i>in silico</i> screening against two critical enzymes (3C-like protease (3CL<sup>pro</sup>) and viral RNA-dependent RNA polymerase (RdRp)), which play important roles in the SARS-CoV-2 life cycle, by using the U.S. Food and Drug Administration (FDA) approved drugs. Our docking simulations enable us to identify several hundred drugs that have high binding affinity for each target. To evaluate persistence of the drugs’ binding to each target near to physiological conditions we selected well tolerated and widely used ones for the molecular dynamics simulations. Simulations results revealed that following drugs were stably interacting with SARS-Cov-2 3CL<sup>pro</sup>: tetracycline and its derivatives, dihydroergotamine, ergotamine, dutasteride, nelfinavir, and paliperidone. A similar analysis with RdRp showed that eltrombopag, tipranavir, ergotamine, and conivaptan were bound with the enzyme during the simulation with high binding energy. Detailed analysis of docking results suggested that ergotamine, dihydroergotamine, bromocriptine, dutasteride, conivaptan, paliperidone, and tipranavir can bind to both enzymes with high affinity. Since these drugs are well tolerated, cost effective and widely used, our study suggested that they have potential to be used in clinical trial for the treatment of SARS-CoV-2 infected patients.</p>
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