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

Abstract

<p>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 focusing on two potential sites (central and terminal sites) 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 substrate-binding pocket. The top hits bound to the central site of Mpro substrate-binding pocket include antiviral drugs such as Darunavir, Nelfinavir and 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. In addition, the top hits bound to the terminal site of Mpro substrate-binding pocket include the anti-asthma drug Montelukast and the anti-histaminic Fexofenadine among others. 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.</p>

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

“…2) were identified as potential candidate treatments of patients with COVID-19, in this study. The remaining seven drugs, including hydroxychloroquine, chloroquine, disulfiram, montelukast sodium, atazanavir, indinavir, and maribavir, were also proposed as potential candidate treatments for patients with COVID-19 in previous studies (6,9,(36)(37)(38). However, within these seven drugs, only disulfiram and atazanavir were previously identified as SARS-CoV-2 M pro inhibitors, whereas the other five drugs were either reported to be active in vitro against SARS-CoV-2 without knowing the specific targets or predicted by computational modeling only without knowing their actual experimental activity.…”

“…The discrepancy between the K i and EC 50 values may be attributed to the possibly imperfect intracellular drug bioavailability such that the intracellular drug concentration is different from the externally added drug concentration. Table 1 (6,36); hydroxychloroquine, chloroquine, and indinavir were reported to be active in vitro against SARS-CoV-2, but their molecular targets were not reported (9,37,39); montelukast sodium and maribavir were only predicted by calculations (37,38) without experimental activity data reported. Disulfiram and atazanavir served as the positive controls for the in vitro activity [in the literature, the IC 50 values for disulfiram and atazanavir were 9.35 and 10 μM, respectively (6,36), and the results of our test were 4.7 and 7.5 μM, respectively, when the same substrate concentration of 20 μM was used].…”

COVID-19 Pandemic: an Overview of epidemiology, pathogenesis, Diagnostics and Potential Vaccines and Therapeutics

“…The development of novel compounds or vaccines that work correctly against SARS-CoV-2 is a time-consuming process. Thus, efforts are focusing on repurposing the use of drugs available on the market to act against SARS-CoV-2 [65][66][67]. Chloroquine and hydroxychloroquine stand as excellent examples and are being adopted at the moment in the standard clinical practices of China for SARS-CoV-2 infection [27].…”

Potential Anti-SARS-CoV-2 Therapeutics That Target the Post-Entry Stages of the Viral Life Cycle: A Comprehensive Review

“…It is being evaluated in the U.S. alone (NCT04456153; n = 60) or in combination with azithromycin in an open-label, non-randomized study in COVID-19 patients at HonorHealth Clinical Research Institute, U.S. (NCT04339426; n = 25). One potential mechanism of action for atovaquone pertaining to SARS-CoV-2 is the inhibition of M pro [ 221 ]. Another computational study suggested that it may inhibit RdRp [ 169 ].…”