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<p>The COVID-19 pandemic continues to impose major global health and economic burdens. This has continued to highlight the need for effective therapeutics. SARS-CoV-2 initiates infection by binding the receptor-binding domain (RBD) of its spike protein to the host angiotensin-converting enzyme 2 (ACE2) receptor. Peptides that bind the RBD can competitively block this interaction and inhibit viral entry at an early stage. In this study, we designed novel inhibitory peptides derived from a wild-type sequence using an integrated computational workflow involving in-silico mutagenesis, molecular docking, and molecular dynamics (MD) simulations. A diverse peptide library was generated through extensive mutagenesis, and top-ranked candidates from docking were further evaluated by MD to assess complex stability and dynamic behavior. Structural and energetic analyses, including RMSD, RMSF, radius of gyration, SASA, hydrogen bonding, PCA, DCCM, and MM/GBSA binding free energy calculations, were used to validate inhibitory potential. The designed peptides (pep1, pep2, and pep3) showed improved binding affinity toward the SARS-CoV-2 RBD compared with the wild-type peptide and maintained stable interactions during simulations. These findings propose promising peptide inhibitors that may disrupt ACE2–RBD binding and support the development of peptide-based therapeutics against COVID-19.</p>

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In-silico design of peptide inhibitors targeting the SARS-CoV-2 spike protein using mutagenesis-based remodelling

  • 期刊论文

  • 发表日期：

    2026年3月21日

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  • Farhan Ullah,
  • Abdus Samad,
  • Shahid Ullah,
  • Peter Chinedu Agu,
  • Na Yang,
  • Ming Lei,
  • Liang Chen,
  • Sheng Wang

摘要

The COVID-19 pandemic continues to impose major global health and economic burdens. This has continued to highlight the need for effective therapeutics. SARS-CoV-2 initiates infection by binding the receptor-binding domain (RBD) of its spike protein to the host angiotensin-converting enzyme 2 (ACE2) receptor. Peptides that bind the RBD can competitively block this interaction and inhibit viral entry at an early stage. In this study, we designed novel inhibitory peptides derived from a wild-type sequence using an integrated computational workflow involving in-silico mutagenesis, molecular docking, and molecular dynamics (MD) simulations. A diverse peptide library was generated through extensive mutagenesis, and top-ranked candidates from docking were further evaluated by MD to assess complex stability and dynamic behavior. Structural and energetic analyses, including RMSD, RMSF, radius of gyration, SASA, hydrogen bonding, PCA, DCCM, and MM/GBSA binding free energy calculations, were used to validate inhibitory potential. The designed peptides (pep1, pep2, and pep3) showed improved binding affinity toward the SARS-CoV-2 RBD compared with the wild-type peptide and maintained stable interactions during simulations. These findings propose promising peptide inhibitors that may disrupt ACE2–RBD binding and support the development of peptide-based therapeutics against COVID-19.