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<p>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&#xa0;kcal/mol, respectively) compared to nirmatrelvir (− 4.85&#xa0;kcal/mol). 100&#xa0;ns molecular dynamics simulations and MM/PBSA calculations revealed DS6 and DS9 with stronger binding free energies (ΔG: − 34.38 and − 33.27&#xa0;kcal/mol) than nirmatrelvir (− 21.10 ± 4.59&#xa0;kcal/mol). Structural analyses (RMSD: 1.80&#xa0;Å for DS6; RoG: 22.34&#xa0;Å; RMSF: 7.19&#xa0;Å) indicated enhanced stability over nirmatrelvir. Per-residue decomposition highlighted key interactions (e.g., HIP41 in DS6: − 46.7&#xa0;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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年11月26日

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  • Segun D. Oladipo,
  • Samuel O. Olalekan,
  • Vincent A. Obakachi,
  • Adesola A. Adeleke,
  • Robert C. Luckay,
  • Abosede A. Badeji

摘要

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.