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

Pectol, D Chase; DeLaney, Christopher R; Zhu, Jiyun; Mellott, Drake M; Katzfuss, Ardala; Taylor, Zane W; Meek, Thomas D; Darensbourg, Marcetta Y

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 (SC2Mpro). In vitro studies indicate inhibition of protease activity upon DNIC treatment, with an IC50 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.