Computational Prediction of Potential Inhibitors of the Main Protease of SARS-CoV-2.

Renata Abel,María Paredes Ramos,Qiaofeng Chen,Monica Rocco,Cameron Mura,Robert Preissner,Horacio Pérez-Sánchez,Paolo Marchetti,Flaminia Coluzzi,Priyanka Banerjee,Maurizio Simmaco,Philip E Bourne

doi:10.3389/fchem.2020.590263

Abstract

The rapidly developing pandemic, known as coronavirus disease 2019 (COVID-19) and caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has recently spread across 213 countries and territories. This pandemic is a dire public health threat—particularly for those suffering from hypertension, cardiovascular diseases, pulmonary diseases, or diabetes; without approved treatments, it is likely to persist or recur. To facilitate the rapid discovery of inhibitors with clinical potential, we have applied ligand- and structure-based computational approaches to develop a virtual screening methodology that allows us to predict potential inhibitors. In this work, virtual screening was performed against two natural products databases, Super Natural II and Traditional Chinese Medicine. Additionally, we have used an integrated drug repurposing approach to computationally identify potential inhibitors of the main protease of SARS-CoV-2 in databases of drugs (both approved and withdrawn). Roughly 360,000 compounds were screened using various molecular fingerprints and molecular docking methods; of these, 80 docked compounds were evaluated in detail, and the 12 best hits from four datasets were further inspected via molecular dynamics simulations. Finally, toxicity and cytochrome inhibition profiles were computationally analyzed for the selected candidate compounds.

Highlights

A novel coronavirus (CoV), known as the severe acute respiratory syndrome coronavirus 2 (SARSCoV-2), began spreading among humans in December 2019 in the city of Wuhan, China, causing a major outbreak of often-fatal pneumonia (Wu et al, 2020)
Recent reports suggest that some U.S Food & Drug Administration (FDA)-approved drugs, remdesivir (Al-Tawfiq et al, 2020) and lopinavir and ritonavir (HIV protease inhibitors) (Cao et al, 2020), may be effective against SARSCoV-2
The crystal structure of the main protease was used as the molecular target for computational docking and protein–ligand interaction analyses; in total, visual inspections were performed for 80 compounds

Summary

Introduction

A novel coronavirus (CoV), known as the severe acute respiratory syndrome coronavirus 2 (SARSCoV-2), began spreading among humans in December 2019 in the city of Wuhan, China, causing a major outbreak of often-fatal pneumonia (Wu et al, 2020). No potent drug or vaccine has been reported (or approved) to treat individuals infected with SARS-CoV-2; only symptomatic treatment has been given to the most critically ill patients. Remdesivir exhibits an antiviral activity with an EC50 of 0.77 μM against SARS-CoV-2, and shorter recovery times (vs a placebo group) were found for adults hospitalized with COVID19 and treated with remdesivir; those patients showed fewer infections of the respiratory tract (Beigel et al, 2020). In March 2020, the WHO launched a “solidarity clinical trials” of repurposed drugs and experimental candidates, wherein testing of the three aforementioned drugs was supplemented with testing of the antimalarial compounds chloroquine and Abbreviations: SARS-CoV-2, severe acute respiratory syndrome coronavirus

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Conclusion