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Dalton Trans ; 50(35): 12226-12233, 2021 Sep 14.
Article in English | MEDLINE | ID: covidwho-1358359

ABSTRACT

Numerous organic molecules are known to inhibit the main protease of SARS-CoV-2, (SC2Mpro), a key component in viral replication of the 2019 novel coronavirus. We explore the hypothesis that zinc ions, long used as a medicinal supplement and known to support immune function, bind to the SC2Mpro enzyme in combination with lipophilic tropolone and thiotropolone ligands, L, block substrate docking, and inhibit function. This study combines synthetic inorganic chemistry, in vitro protease activity assays, and computational modeling. While the ligands themselves have half maximal inhibition concentrations, IC50, for SC2Mpro in the 8-34 µM range, the IC50 values are ca. 100 nM for Zn(NO3)2 which are further enhanced in Zn-L combinations (59-97 nM). Isolation of the Zn(L)2 binary complexes and characterization of their ability to undergo ligand displacement is the basis for computational modeling of the chemical features of the enzyme inhibition. Blind docking onto the SC2Mpro enzyme surface using a modified Autodock4 protocol found preferential binding into the active site pocket. Such Zn-L combinations orient so as to permit dative bonding of Zn(L)+ to basic active site residues.


Subject(s)
COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Tropolone/pharmacology , Zinc/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/virology , Catalytic Domain/drug effects , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Humans , Ligands , Models, Molecular , Molecular Docking Simulation , Protease Inhibitors/chemistry , SARS-CoV-2/enzymology , Tropolone/analogs & derivatives , Zinc/chemistry
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