Repurposing Antiviral Drugs to Inhibit SARS-CoV-2 Papin-Like Protease Activity

Since December 2019, a pneumonia caused by a novel coronavirus (SARS-CoV-2) emerged in China and has rapidly spread around the world. The virus has caused a global outbreak of viral pneumonia, which has been known as coronavirus disease (COVID-19). This study aims to examine known direct acting antivirals (DAA) against SARS-CoV-2 papin like protease. A number of known antiviral drugs were tested as potential SARS-CoV-2 virus inhibitors using the molecular docking analysis to examine the free natural affinity of the binding ligand to catalytic residues and substrate binding pockets without forcing the docking of ligand to active site. SARS-CoV-2 papin like protease solved structure (PDB ID: 6W9C) is targeted by direct acting antiviral drugs. The geometry of all inhibitors was optimized using Avogadro software. Molecular Docking was performed using AutoDock Vina software. Protein-Ligand Interaction Profiler (PLIP) web server was used to analyze the interactions formed between drugs and SARS-CoV-2 PLpro. Mycophenolic acid and 4′-Tosyl Mycophenolic Acid-d3 was tested against SARS-CoV-2 papin like protease mutant C111S (PDB ID: 6WRH). Mycophenolic acid showed mild efficacy against the mutant strain. The molecular docking analysis results indicated that Mycophenolic acid and 4′-Tosyl Mycophenolic Acid-d3 has good binding affinities to the protein drug target (-5.72 Kcal/mol and -5.72 Kcal/mol) and showed the highest probabilities to bind to catalytic residues of target protein (30% and 50%) respectively, suggesting their potential use for COVID-19 treatment. Molecular dynamic simulation was used to confirm the stability of the complexes formed.