Copper(II) Inhibition of the SARS‐CoV‐2 Main Protease
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 H...
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Wiley-VCH
2025-07-01
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| Series: | Natural Sciences |
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| Online Access: | https://doi.org/10.1002/ntls.70012 |
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| author | Roberto A. Garza‐López Liam Kwak Andrew Chung Gabriel L. Ancajas John J. Kozak Harry B. Gray |
| author_facet | Roberto A. Garza‐López Liam Kwak Andrew Chung Gabriel L. Ancajas John J. Kozak Harry B. Gray |
| author_sort | Roberto A. Garza‐López |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-344db3f23f894529b5cdf81de0725819 |
| institution | DOAJ |
| issn | 2698-6248 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Wiley-VCH |
| record_format | Article |
| series | Natural Sciences |
| spelling | doaj-art-344db3f23f894529b5cdf81de07258192025-08-20T03:08:18ZengWiley-VCHNatural Sciences2698-62482025-07-0153n/an/a10.1002/ntls.70012Copper(II) Inhibition of the SARS‐CoV‐2 Main ProteaseRoberto A. Garza‐López0Liam Kwak1Andrew Chung2Gabriel L. Ancajas3John J. Kozak4Harry B. Gray5Department of Chemistry and Seaver Chemistry Laboratory Pomona College Claremont California USADepartment of Chemistry and Seaver Chemistry Laboratory Pomona College Claremont California USADepartment of Chemistry and Seaver Chemistry Laboratory Pomona College Claremont California USADepartment of Chemistry and Seaver Chemistry Laboratory Pomona College Claremont California USADepartment of Chemistry DePaul University Chicago Illinois USABeckman Institute California Institute of Technology Pasadena California USAABSTRACT 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.https://doi.org/10.1002/ntls.70012a) Metal‐based compounds function as inhibitors to combat infectious diseases, including COVID‐19. b) Docking and molecular dynamics simulations confirm the stability of Cu(II) chelate binding. c) Cu(II) complexes are biologically compatible and could inhibit viruses. |
| spellingShingle | Roberto A. Garza‐López Liam Kwak Andrew Chung Gabriel L. Ancajas John J. Kozak Harry B. Gray Copper(II) Inhibition of the SARS‐CoV‐2 Main Protease Natural Sciences a) Metal‐based compounds function as inhibitors to combat infectious diseases, including COVID‐19. b) Docking and molecular dynamics simulations confirm the stability of Cu(II) chelate binding. c) Cu(II) complexes are biologically compatible and could inhibit viruses. |
| title | Copper(II) Inhibition of the SARS‐CoV‐2 Main Protease |
| title_full | Copper(II) Inhibition of the SARS‐CoV‐2 Main Protease |
| title_fullStr | Copper(II) Inhibition of the SARS‐CoV‐2 Main Protease |
| title_full_unstemmed | Copper(II) Inhibition of the SARS‐CoV‐2 Main Protease |
| title_short | Copper(II) Inhibition of the SARS‐CoV‐2 Main Protease |
| title_sort | copper ii inhibition of the sars cov 2 main protease |
| topic | a) Metal‐based compounds function as inhibitors to combat infectious diseases, including COVID‐19. b) Docking and molecular dynamics simulations confirm the stability of Cu(II) chelate binding. c) Cu(II) complexes are biologically compatible and could inhibit viruses. |
| url | https://doi.org/10.1002/ntls.70012 |
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