Dinitrosyl iron complexes (DNICs) as inhibitors of the SARS-CoV-2 main protease

By repurposing DNICs designed for other medicinal purposes, the possibility of protease inhibition was investigated in silico using AutoDock 4.2.6 (AD4) and in vitro via a FRET protease assay. AD4 was validated as a predictive computational tool for coordinatively unsaturated DNIC binding using the only known crystal structure of a protein-bound DNIC, PDB- 1ZGN (calculation RMSD = 1.77). From the in silico data the dimeric DNICs TGTA-RRE, [(μ-S-TGTA)Fe(NO) 2 ] 2 (TGTA = 1-thio- β - d -glucose tetraacetate) and TG-RRE, [(μ-S-TG)Fe(NO) 2 ] 2 (TG = 1-thio- β - d -glucose) were identified as promising leads for inhibition via coordinative inhibition at Cys-145 of the SARS-CoV-2 Main Protease (SC2M pro ). In vitro studies indicate inhibition of protease activity upon DNIC treatment, with an IC 50 of 38 ± 2 μM for TGTA-RRE and 33 ± 2 μM for TG-RRE. This study presents a simple computational method for predicting DNIC-protein interactions; the in vitro study is consistent with in silico leads. By repurposing DNICs designed for other medicinal purposes, the possibility of protease inhibition was investigated in silico using AutoDock 4.2.6 (AD4) and in vitro via a FRET protease assay.