Thiuram disulfides as prospective inhibitors of 3-chymotrypsin-like cysteine protease: an in-silico approach targeting SARS-CoV-2.

The COVID-19 pandemic, caused by SARS-CoV-2, requires effective therapeutics targeting the 3-chymotrypsin-like cysteine protease (3CLpro), essential for viral replication. This in-silico study evaluates 12 thiuram disulfides as potential 3CLpro inhibitors. Molecular docking identified DS4, DS6, and DS9 with superior binding affinities (Glide scores: - 5.80, - 5.11, and - 5.17 kcal/mol, respectively) compared to nirmatrelvir (- 4.85 kcal/mol). 100 ns molecular dynamics simulations and MM/PBSA calculations revealed DS6 and DS9 with stronger binding free energies (ΔG: - 34.38 and - 33.27 kcal/mol) than nirmatrelvir (- 21.10 ± 4.59 kcal/mol). Structural analyses (RMSD: 1.80 Å for DS6; RoG: 22.34 Å; RMSF: 7.19 Å) indicated enhanced stability over nirmatrelvir. Per-residue decomposition highlighted key interactions (e.g., HIP41 in DS6: - 46.7 kcal/mol electrostatic). Toxicity predictions via pkCSM showed non-mutagenicity, non-hepatotoxicity, and no skin sensitization. Dynamic cross-correlation analysis suggested allosteric effects influencing conformational flexibility. Thiuram disulfides, especially DS6 and DS9, exhibit promise as 3CLpro inhibitors, warranting further experimental validation. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-025-00496-1.