Structural similarities between SARS-CoV2 3CLpro and other viral proteases suggest potential lead molecules for developing broad spectrum antivirals

Khushboo Bafna, Christopher L. Cioffi, Robert M. Krug, Gaetano T. Montelione

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Considering the significant impact of the recent COVID-19 outbreak, development of broad-spectrum antivirals is a high priority goal to prevent future global pandemics. Antiviral development processes generally emphasize targeting a specific protein from a particular virus. However, some antiviral agents developed for specific viral protein targets may exhibit broad spectrum antiviral activity, or at least provide useful lead molecules for broad spectrum drug development. There is significant potential for repurposing a wide range of existing viral protease inhibitors to inhibit the SARS-CoV2 3C-like protease (3CLpro). If effective even as relatively weak inhibitors of 3CLpro, these molecules can provide a diverse and novel set of scaffolds for new drug discovery campaigns. In this study, we compared the sequence- and structure-based similarity of SARS-CoV2 3CLpro with proteases from other viruses, and identified 22 proteases with similar active-site structures. This structural similarity, characterized by secondary-structure topology diagrams, is evolutionarily divergent within taxonomically related viruses, but appears to result from evolutionary convergence of protease enzymes between virus families. Inhibitors of these proteases that are structurally similar to the SARS-CoV2 3CLpro protease were identified and assessed as potential inhibitors of SARS-CoV2 3CLpro protease by virtual docking. Several of these molecules have docking scores that are significantly better than known SARS-CoV2 3CLpro inhibitors, suggesting that these molecules are also potential inhibitors of the SARS-CoV2 3CLpro protease. Some have been previously reported to inhibit SARS-CoV2 3CLpro. The results also suggest that established inhibitors of SARS-CoV2 3CLpro may be considered as potential inhibitors of other viral 3C-like proteases.

Original languageEnglish (US)
Article number948553
JournalFrontiers in Chemistry
StatePublished - Oct 6 2022

All Science Journal Classification (ASJC) codes

  • General Chemistry


  • 3CL (Mpro)
  • COVID-19
  • drug discovery
  • structural bioinformatics
  • structure based dendrograms
  • topology diagrams
  • viral protease inhibitors
  • virtual docking


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