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

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.