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>

Identification of saquinavir as a potent inhibitor of dimeric SARS-CoV2 main protease through MM/GBSA

“…Comparative analysis of the affinity tendency observed for three of the 12 evaluated compounds previously reported by Farag et al (Darunavir > rosuvastatin > saquinavir) [8], Chen et al (ledipasvir > velpatasvir) [9], Adem et al (hesperidin > rutin > diosmin) [35], and Kumar et al (tipranavir > raltegravir) [10] revealed discrepancies when compared with our findings. These observations highlight the degree to which the computational strategy employed to identify potential inhibitors of SARS-CoV M pro impacted affinity tendency, and underscored the utility of combining docking, MD simulations and end-point binding free energy methods.…”

“…in previous studies that virtually screened candidates targeting monomeric SARS-CoV2 M pro[8][9][10][11]. Of the 12 FDA approved drugs identified, darunavir, indinavir, saquinavir and tipranavir are HIV protease inhibitors, and…”

Bepridil is potent against SARS-CoV-2 In Vitro

“…Some of the small molecule medicines used in our docking study were previously reported in other computational studies. [15][16][17][18] Autodock was the program we adopted for the docking analysis. 21 The covalent ligand and non-bonded small molecules in the structure of 6LU7 was removed for the preparation of the protein structure for the docking.…”

“…Since the release of the first M Pro crystal structure, many computational studies have been carried out to screen existing drugs in their inhibition of M Pro and many potent leads have been proposed. [15][16][17][18] However, most of these lead drugs have not yet been confirmed experimentally. To investigate whether some existing drugs can potently inhibit M Pro , we have docked a group of selected FDA/EMA-approved small molecule medicines to the active site of M Pro and selected about 30 hit drugs to characterize their inhibition on M Pro experimentally.…”

Drug Binding Dynamics of the Dimeric SARS-CoV-2 Main Protease, Determined by Molecular Dynamics Simulation

“…Furthermore, it has been recently reported that nelfinavir had anti-SARS-CoV-2 activity, as demonstrated in a cell-based experimental assay [12,13]. In addition, other HIV protease inhibitors such as indinavir, darunavir, and saquinavir, have been proposed as drug candidates against SARS-CoV-2 M pro , using computational studies [14][15][16][17][18]. These HIV protease inhibitors are repurposed drug candidates, some of which are already being tested in clinical trials.…”