Near-physiological-temperature serial crystallography reveals conformations of SARS-CoV-2 main protease active site for improved drug repurposing

Structure. 2021 Dec 2;29(12):1382-1396.e6. doi: 10.1016/j.str.2021.07.007. Epub 2021 Aug 16.


The COVID-19 pandemic has resulted in 198 million reported infections and more than 4 million deaths as of July 2021 ( Research to identify effective therapies for COVID-19 includes: (1) designing a vaccine as future protection; (2) de novo drug discovery; and (3) identifying existing drugs to repurpose them as effective and immediate treatments. To assist in drug repurposing and design, we determine two apo structures of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease at ambient temperature by serial femtosecond X-ray crystallography. We employ detailed molecular simulations of selected known main protease inhibitors with the structures and compare binding modes and energies. The combined structural and molecular modeling studies not only reveal the dynamics of small molecules targeting the main protease but also provide invaluable opportunities for drug repurposing and structure-based drug design strategies against SARS-CoV-2.

Keywords: SARS-CoV-2; SFX; ambient temperature; drug repurposing; main protease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • COVID-19 Drug Treatment*
  • Catalytic Domain
  • Computer Simulation
  • Coronavirus 3C Proteases / chemistry*
  • Crystallography, X-Ray
  • Dimerization
  • Drug Design*
  • Drug Repositioning*
  • Molecular Conformation
  • Molecular Docking Simulation
  • Principal Component Analysis
  • Protein Conformation
  • Recombinant Proteins / chemistry
  • SARS-CoV-2*
  • Temperature


  • Recombinant Proteins
  • 3C-like proteinase, SARS-CoV-2
  • Coronavirus 3C Proteases