Discovery of COVID-19 Inhibitors Targeting the SARS-CoV-2 Nsp13 Helicase

J Phys Chem Lett. 2020 Nov 5;11(21):9144-9151. doi: 10.1021/acs.jpclett.0c02421. Epub 2020 Oct 14.


The raging COVID-19 pandemic caused by SARS-CoV-2 has infected tens of millions of people and killed several hundred thousand patients worldwide. Currently, there are no effective drugs or vaccines available for treating coronavirus infections. In this study, we have focused on the SARS-CoV-2 helicase (Nsp13), which is critical for viral replication and the most conserved nonstructural protein within the coronavirus family. Using homology modeling that couples published electron-density with molecular dynamics (MD)-based structural refinements, we generated structural models of the SARS-CoV-2 helicase in its apo- and ATP/RNA-bound conformations. We performed virtual screening of ∼970 000 chemical compounds against the ATP-binding site to identify potential inhibitors. Herein, we report docking hits of approved human drugs targeting the ATP-binding site. Importantly, two of our top drug hits have significant activity in inhibiting purified recombinant SARS-CoV-2 helicase, providing hope that these drugs can be potentially repurposed for the treatment of COVID-19.

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / metabolism
  • Amino Acid Sequence
  • Antiviral Agents / chemistry*
  • Antiviral Agents / metabolism
  • Antiviral Agents / therapeutic use
  • Betacoronavirus / enzymology*
  • Betacoronavirus / isolation & purification
  • Binding Sites
  • COVID-19
  • Coronavirus Infections / drug therapy
  • Coronavirus Infections / virology
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Molecular Dynamics Simulation
  • Pandemics
  • Pneumonia, Viral / drug therapy
  • Pneumonia, Viral / virology
  • Protein Structure, Tertiary
  • RNA Helicases / antagonists & inhibitors*
  • RNA Helicases / chemistry
  • RNA Helicases / metabolism
  • SARS-CoV-2
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / chemistry
  • Viral Nonstructural Proteins / metabolism


  • Antiviral Agents
  • Viral Nonstructural Proteins
  • Adenosine Triphosphate
  • RNA Helicases