Discovery of COVID-19 Inhibitors Targeting the SARS-CoV-2 Nsp13 Helicase.
Mark Andrew WhiteWei LinXiaodong ChengPublished in: The journal of physical chemistry letters (2020)
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.
Keyphrases
- sars cov
- molecular dynamics
- respiratory syndrome coronavirus
- end stage renal disease
- density functional theory
- chronic kidney disease
- cancer therapy
- coronavirus disease
- randomized controlled trial
- systematic review
- transcription factor
- small molecule
- signaling pathway
- emergency department
- prognostic factors
- drug delivery
- risk assessment
- molecular dynamics simulations
- replacement therapy
- single cell
- patient reported
- electronic health record