Copper(II) Inhibition of the SARS-CoV-2 Main Protease
Creators
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1.
Pomona College
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2.
DePaul University
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3.
California Institute of Technology
Abstract
In an analysis of the structural stability of the coronavirus main protease (Mpro), we identified regions of the protein that could be disabled by cobalt(III)-cation binding to histidines and cysteines. Here we have extended our work to include copper(II) chelates, which we have docked to HIS 41 and CYS 145 in the Mpro active-site region. We have found stable docked structures where Cu(II) could readily bond to the CYS 145 thiolate, which would be lethal to the enzyme. We investigated the structural basis of Cu(II) Schiff-base chelates as potential Mpro inhibitors in silico. Using induced-fit docking (IFD) and molecular dynamics (MD) simulations, we identified the binding mode and assessed the stability of Mpro inhibition. Our results show that Cu(II) chelates form stable complexes with HIS 41 and CYS 145, with Cu(II) bonding to the CYS 145 thiolate. This irreversible binding is anticipated to effectively inhibit Mpro activity, thereby preventing the proteolytic processing of the SARS-CoV-2 polyprotein into functional proteins necessary for viral activity. Our findings suggest that Cu(II) Schiff-base chelates are promising candidates for the irreversible inhibition of SARS-CoV-2 Mpro.
Copyright and License
© 2025 The Author(s). Natural Sciences published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Acknowledgement
Work at Caltech was supported by the Arnold and Mabel Beckman Foundation. Support at Pomona College was provided by the Howard Hughes Medical Institute Research Program, a Sontag Research Fellowship Award and a Hirsch Research Initiation Grant. Molecular graphics and analyses were performed with UCSF Chimera, UCSF ChimeraX, and PyMOL. UCSF Chimera was developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from NIH P41-GM103311. UCSF ChimeraX was developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from National Institutes of Health R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases. PyMOL was created and distributed by Schrödinger, LLC.
Supplemental Material
Supplementary information. See attached: ntls70012-sup-0001-suppmat.pdf
Files
Natural Sciences - 2025 - Garza‐López - Copper II Inhibition of the SARS‐CoV‐2 Main Protease.pdf
Additional details
Related works
- Is new version of
- Discussion Paper: 10.26434/chemrxiv.12673436.v1 (DOI)
Funding
- Howard Hughes Medical Institute (HHMI)
- Arnold and Mabel Beckman Foundation
- Sontag Foundation
- National Institutes of Health
- R01-GM129325
Dates
- Available
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2025-05-26Published online
Caltech Custom Metadata
- Caltech groups
- COVID-19 , Division of Chemistry and Chemical Engineering (CCE)
- Publication Status
- Published