Abstract
Since the outbreak of the COVID-19 pandemic in December 2019 and its rapid spread worldwide, the scientific community has been under pressure to react and make progress in the development of an effective treatment against the virus responsible for the disease. Here, we implement an original virtual screening (VS) protocol for repositioning approved drugs in order to predict which of them could inhibit the main protease of the virus (M-pro), a key target for antiviral drugs given its essential role in the virus’ replication. Two different libraries of approved drugs were docked against the structure of M-pro using Glide, FRED and AutoDock Vina, and only the equivalent high affinity binding modes predicted simultaneously by the three docking programs were considered to correspond to bioactive poses. In this way, we took advantage of the three sampling algorithms to generate hypothetic binding modes without relying on a single scoring function to rank the results. Seven possible SARS-CoV-2 M-pro inhibitors were predicted using this approach: Perampanel, Carprofen, Celecoxib, Alprazolam, Trovafloxacin, Sarafloxacin and ethyl biscoumacetate. Carprofen and Celecoxib have been selected by the COVID Moonshot initiative for in vitro testing; they show 3.97 and 11.90% M-pro inhibition at 50 µM, respectively.
Highlights
The recently worldwide pandemic named COVID-19 (COronaVIrus Disease 2019) has spread rapidly since it emerged in Wuhan (China) in December 2019
Two different libraries of approved drugs were docked against the structure of main protease of the virus (M-pro) using Glide, FRED and AutoDock Vina, and only the equivalent high affinity binding modes predicted simultaneously by the three docking programs were considered to correspond to bioactive poses
The following libraries were used as a reference to establish key residue interactions and docking score cutoffs: (a) OTAVA-ML-SARS: library from OTAVA which contains 1577 compounds with predicted activity against SARS-CoV-2 based on machine learning approaches [44]; (b) OTAVA-SARS-CoV-2: library from OTAVA which contains 1017 compounds with predicted activity against SARS-CoV-2 M-pro based on receptor-based virtual screening (VS) [44]; (c) COVID-Moonshot: library of 551 compounds mainly designed from cocrystallized drug fragments with SARS-CoV-2 M-pro and sent to COVID Moonshot before April 2020 [45]; and (d) DD-top-1000: a set of 1000 potential ligands for M-pro recently identified by applying Deep Docking to the ZINC15 database [46] and made publicly available by Ton et al [5]
Summary
The recently worldwide pandemic named COVID-19 (COronaVIrus Disease 2019) has spread rapidly since it emerged in Wuhan (China) in December 2019. SARS-CoV-2 has been identified as the pathogen responsible for the outbreak of an atypical pneumonia whose symptoms range from mild effects such as fever, dry cough, fatigue, dyspnea, difficulty breathing, to severe progressive pneumonia, multiorgan failure and death [1]. Since the outbreak of SARS-CoV-2, the World Health Organization (WHO) has declared a state of global health emergency. As of the 15th of May 2020, the total number of confirmed cases of COVID-19 has risen to 4,434,590 in at least 188 different countries. The risk of severe cases increases in elderly patients with previous pathologies, such as heart failure or diabetes (i.e., 89.5% of deaths in Italy for COVID-19 have been among people over 70 years old) [3]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
