Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents

• Published in: Communications biology 2021-01, Vol.4 (1), p.93-93, Article 93
• Main Authors: Mody, Vicky, Ho, Joanna, Wills, Savannah, Mawri, Ahmed, Lawson, Latasha, Ebert, Maximilian C. C. J. C., Fortin, Guillaume M., Rayalam, Srujana, Taval, Shashidharamurthy
• Format: Article
• Language: English
• Subjects: 101/47; 631/154/1435/2163; 631/154/309/507; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biology; Biomedical and Life Sciences; Chymotrypsin; Computer applications; Coronavirus 3C Proteases - antagonists & inhibitors; Coronavirus 3C Proteases - chemistry; Coronavirus 3C Proteases - metabolism; Coronaviruses; COVID-19 - drug therapy; COVID-19 - virology; Cysteine Proteinase Inhibitors - chemistry; Cysteine Proteinase Inhibitors - pharmacology; Drug Discovery; Drugs; Enzymatic activity; Enzymes; Humans; Ivermectin; Life Sciences; Ligands; Micafungin; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; Molecular modelling; Morbidity; Protein Binding; Protein Conformation; Proteinase; Proteinase inhibitors; Public health; Replication; SARS-CoV-2 - drug effects; SARS-CoV-2 - enzymology; Severe acute respiratory syndrome coronavirus 2; Structure-Activity Relationship; Virus Replication - drug effects
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-020-01577-x

Emerging outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is a major threat to public health. The morbidity is increasing due to lack of SARS-CoV-2 specific drugs. Herein, we have identified potential drugs that target the 3-chymotrypsin like protease (3CLpro), the main protease that is pivotal for the replication of SARS-CoV-2. Computational molecular modeling was used to screen 3987 FDA approved drugs, and 47 drugs were selected to study their inhibitory effects on SARS-CoV-2 specific 3CLpro enzyme in vitro. Our results indicate that boceprevir, ombitasvir, paritaprevir, tipranavir, ivermectin, and micafungin exhibited inhibitory effect towards 3CLpro enzymatic activity. The 100 ns molecular dynamics simulation studies showed that ivermectin may require homodimeric form of 3CLpro enzyme for its inhibitory activity. In summary, these molecules could be useful to develop highly specific therapeutically viable drugs to inhibit the SARS-CoV-2 replication either alone or in combination with drugs specific for other SARS-CoV-2 viral targets. Here, the authors identify potential drugs that target 3-chymotrypsin like protease (3CLpro), which is a pivotal protease for the replication of SARS-CoV-2. They found that off-target inhibitors such as ivermectin and micafungin inhibit 3CLpro enzyme activity, suggesting that these molecules could constitute useful therapies to inhibit SARS-CoV-2 replication.