<br/>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.1,2 They are particularly effective when reactive centers permits covalent attachment. We explore the hypothesis that coordinate covalent bonds with suitably ligated metal ions, in particular iron, cobalt and zinc,1-2 should bind to the histidine and cysteine rich SC2Mpro enzyme in synergy with lipophilic tropolone derivatives (L), block substrate docking, and inhibit function. Synthetic chemistry, enzyme inhibition assays of various combinations of metal and ligand and computational studies (AutoDock and QM/MM) are interpreted according to this hypothesis. To enhance ligand affinity for the transition metal ions and avoid toxic “free” metal concentrations, thiolated derivatives of Tropolone and Hinokitiol were synthesized and compared to their unmodified parent compounds for the inhibition of SC2Mpro . Inhibition constants, IC50 values, and computational modeling via AutoDock4 and QM/MM methodologies indicate that the most plausible mode of inhibition via such M-L combinations involves dative bonding of M(L)+ to basic active site residues.

Metal/ligand synergy in transition metal tropolone and thiotropolone combinations as potential therapeutics for SARS-CoV-2

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.