key: cord-0014104-3ufnt49p
authors: Garza-Lopez, Roberto A.; Kozak, John J.; Gray, Harry B.
title: Copper(II) Inhibition of the SARS-CoV-2 Main Protease
date: 2020-07-21
journal: ChemRxiv
DOI: 10.26434/chemrxiv.12673436
sha: fca54ed581a164b24495a628311ac2842f578498
doc_id: 14104
cord_uid: 3ufnt49p

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 [1]. 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 also started studying the Spike Protein, PDB ID: 6VXX and the region around the D614G mutant.

. Chimera representation of the SARS-CoV-2 homodimer structure (PDB code: 6LU7).

Of the seven histidines in the protease monomer, HIS 41 is in the most stable region of the native structure [1] . Metal-ion binding to the imidazole side chain of this histidine would break up the internal H-bond network (Figure 2 ), which would disable the enzyme. Other residues that could be targeted include HIS 163 and HIS 164, as they also are in relatively stable regions [1] .

Among metal complex candidates that might bind in this region, [Co(acacen)(NH3)2] + is particularly attractive, as it is known to inhibit other proteases by HIS-imidazole displacement of one or both axial ammines [18, 19] . We suggest that experiments using an excess of [Co(acacen)(NH3)2] + should be tried. If the protease is flooded with this cation, binding to at least 3 histidines could occur. Binding a cationic metal complex to several histidines would make the surface more hydrophilic, which in turn could trigger unfolding, as documented in our work on Co(III) binding to myoglobin [20] . Cobalt and copper ligation to cysteines other than CYS 145 also should be explored. Of the 12 cysteines in the protease monomer, arguably the most attractive target is CYS 44, which is on a very stable helix [1] . Displacement of an axial ammine in [Co(acacen)(NH3)2] + by the CYS 44 thiolate would trigger partial helical unfolding, which could disrupt protease function.

We also are studying the Spike protein ( Figure 6 ), a trimer with many cysteines and histidines that are exposed to solvent [23] . We are testing the proposal that cobalt(III) or copper(II) binding to these residues would partially unfold the protein, including the region around GLY 614 in the D614G mutant. 6VXX. [23, 24] Concluding Remarks.

We have identified several very attractive histidine and cysteine targets for protease inhibiton by inorganic therapeutic agents. In one scenario, cobalt and copper binding to histidines could unfold the main protease. In others, the protease could be disabled by Cu-S bonding in Cu(II)Lm conjugates.

Supporting Information Figure S1 : Chimera representation of Cu(II)Lm docked near HIS 41 in Mpro (PDB code 6Y2E) with a binding energy of 6.8 kcal/mol. Inset: Cu(II) chelation; Cu-S(CYS 145) = 3.472 Å. The ligand and receptor files were prepared using the molecular docking program AutoDock Vina [22] . The amino acid HIS 41 is enclosed in the green box. AutoDock Vina predicts the bound conformations and the binding affinities (kcal/mol) within that space. The different poses were visualized via Chimera 

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Work at Caltech was supported by the Arnold and Mabel Beckman Foundation. Support at