Repurposing approved drugs as potential inhibitors of 3CL-protease of SARS-CoV-2: Virtual screening and structure based drug design

Comput Biol Chem. 2020 Oct:88:107351. doi: 10.1016/j.compbiolchem.2020.107351. Epub 2020 Jul 31.

Abstract

3CL proteases (3CLpro) are only found in RNA viruses and have a central role in polyprotein processing during replication. Therefore, 3CLpro has emerged as promising drug target for therapeutic treatment of infections caused by Coronaviruses. In the light of the recent major outbreak of the SARS-CoV-2 virus and the continuously rising numbers of infections and casualties, there is an urgent need for quickly available drugs or vaccines to stop the current COVID-19 pandemic. Repurposing of approved drugs as 3CLpro inhibitors could dramatically shorten the period up to approval as therapeutic against SARS-CoV-2, since pharmacokinetics and toxicity is already known. Several known drugs, e.g. oxytetracycline, doxorubicin, kanamycin, cefpiramide, teniposide, proanthocyanidin and salvianolic acid B, but also not-approved active compounds from the ZINC15 library were identified as new potential inhibitors of 3CLpro by using different complementary virtual screening and docking approaches. These compounds have the potential to be further optimized using structure based drug design as demonstrated for oxytetracycline.

Keywords: Antiviral; C30 endopeptidase; COVID-19; Docking; Drug discovery; Pharmacophore; Therapeutic.

MeSH terms

  • Betacoronavirus / drug effects
  • Betacoronavirus / enzymology*
  • COVID-19
  • Coronavirus 3C Proteases
  • Coronavirus Infections / drug therapy*
  • Cysteine Endopeptidases
  • Databases, Factual
  • Drug Design*
  • Drug Repositioning*
  • Humans
  • Models, Molecular
  • Molecular Docking Simulation
  • Pandemics
  • Pneumonia, Viral / drug therapy*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Protein Conformation
  • SARS-CoV-2
  • Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

  • Protease Inhibitors
  • Viral Nonstructural Proteins
  • Cysteine Endopeptidases
  • Coronavirus 3C Proteases