TY - JOUR
T1 - Discovery of COVID-19 Inhibitors Targeting the SARS-CoV-2 Nsp13 Helicase
AU - White, Mark Andrew
AU - Lin, Wei
AU - Cheng, Xiaodong
N1 - Funding Information:
We thank Professor Jian-Dong Huang from The University of Hong Kong for providing the expression vector for SARS-CoV Nsp 13 helicase. This work is supported by grant from the National Institute of Health R35GM122536, and in part, through a Sealy and Smith Foundation grant to the Sealy Center for Structural Biology and Molecular Biophysics. The authors acknowledge the Texas Advanced Computing Center (TACC) at The University of Texas at Austin for providing HPC resources that have contributed to the research results reported within this paper (URL: http://www.tacc.utexas.edu ). Special thanks to Drs. Stan Watowich (UTMB) and Joe Allen (TACC) for their help with the Drug Discovery Portal at the TACC.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85095799485&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85095799485&partnerID=8YFLogxK
U2 - 10.1021/acs.jpclett.0c02421
DO - 10.1021/acs.jpclett.0c02421
M3 - Article
C2 - 33052685
AN - SCOPUS:85095799485
SP - 9144
EP - 9151
JO - Journal of Physical Chemistry Letters
JF - Journal of Physical Chemistry Letters
SN - 1948-7185
ER -