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. (20th September 2022) - Singh, B. G.
Abstract : Among the 22 organoselenium compounds studied, 2-Py2 Se2 & Nict2 Se2 showed the highest affinity for M pro . The biochemical studies confirmed their superiority as compared to standard compound like Ebselen in terms of the IC50 required for M pro inhibition. 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 (Nict2 Se2 ) and pyridine diselenide (2-Py2 Se2 ) with binding affinities in the range of ∼10 5 M −1, were subjected to biochemical evaluation. The IC50 values of Nict2 Se2 and 2-Py2 Se2 for M pro inhibition estimated by bioassay were ∼ 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, Nict2 Se2 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 Nict2 Se2 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.