Zinc thiotropolone combinations as inhibitors of the SARS-CoV-2 main protease

Abstract

Numerous organic molecules are known to inhibit the main protease of SARS-CoV-2, (SC2M^pro), a key component in viral replication of the 2019 novel coronavirus. We explore the hypothesis that zinc ions, <i>long used as a medicinal supplement and known to support immune function</i>, bind to the SC2M^pro enzyme in combination with lipophilic tropolone and thiotropolone ligands, <b>L</b>, block substrate docking, and inhibit function. This study combines synthetic inorganic chemistry, <i>in vitro</i> protease activity assays, and computational modeling. While the ligands themselves have half maximal inhibition concentrations, IC₅₀, for SC2M^pro in the 8-34 μM range, the IC₅₀ values are <i>ca.</i> 100 nM for Zn(NO₃)₂ which are further enhanced in Zn-<b>L</b> combinations (59-97 nM). Isolation of the Zn(<b>L</b>)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 SC2M^pro enzyme surface using a modified Autodock4 protocol found preferential binding into the active site pocket. Such Zn-<b>L</b> combinations orient so as to permit dative bonding of Zn(<b>L</b>)⁺ to basic active site residues.