Identification of a pyridine derivative of diselenides as a potent inhibitor of the main protease of SARS-CoV-2 through in silico screening and biochemical evaluation

ABSTRACT

Coronavirus induced disease-19 caused by SARS-CoV-2 has presented an unprecedented health and economic crisis worldwide. Substantial progress has been made in the last two years to develop vaccines against SARS-CoV-2. Along with vaccines, antiviral drugs constitute the secondary line of defense against the viral pathogen. Viral proteins are considered to be promising targets for designing antiviral drugs. The main protease (M-pro) is known to play a significant role in SARS-CoV-2 replication within the host. Accordingly, in the present study, a series of selenium-containing amino acids, selenopyridines and their respective derivatives, were screened for interaction with M-pro (PDB code 6LU7) by molecular docking approach. The most potent docked compounds, namely nicotinamide diselenide (Nict(2)Se(2)) and pyridine diselenide (2-Py2Se2) with binding affinities in the range of similar to 10(5) M-1, were subjected to biochemical evaluation. The IC50 values of Nict(2)Se(2) and 2-Py2Se2 for M-pro inhibition estimated by bioassay were similar to 516.0 +/- 0.02 nM and 69.4 +/- 0.03 nM, respectively. The toxicity evaluation in a normal lung fibroblast (WI38) cell line suggested that among the above two compounds, Nict(2)Se(2) was much safer for biological applications. The circular dichroism studies and competitive kinetic assay using 5,5-dithio-bis-(2-nitrobenzoic acid) as a substrate suggested that Nict(2)Se(2) treatment induced structural deformation of M-pro probably through interacting with a cysteine residue present in its active site. Together, the present investigation proposes that organoselenium compounds comprising aromatic amide moieties connected by a diselenide bridge could be potential candidate molecules for the future design of antiviral drugs specifically against SARS-CoV-2.