Targeting the main SARS-Cov-2 pathways with peptide inhibitors by molecular docking and molecular simulation approaches.

[Display omitted] • Designing new peptides to combat SARS-CoV-2 Omicron variant. • Employing advanced computational methods for peptide design. • Identifying key role of hydrophobic forces in peptide binding. • Pep11 as a potent inhibitor with high omicron RBD affinity. • Molecular-level analysis of interactions in liquid phase. The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a significant global health crisis. The virus's spike glycoprotein (S protein) plays a pivotal role in facilitating viral entry and enhancing infectivity. In this study, we aimed to design peptides that can inhibit the interaction between the Omicron SARS-CoV-2 spike protein and its receptor ACE2, thereby preventing viral pathogenesis. We employed computational methods, including molecular docking and molecular dynamics simulations, to design and assess the binding affinity of peptide inhibitors. The crystal structure of the receptor-binding domain (RBD)-ACE2 complex was used as a template for peptide design. The designed peptides were evaluated for their stability, interaction strength, and binding affinity through molecular dynamics simulations. A library of peptide candidates was constructed, considering mutations that enhance binding affinity. The toxicity and allergenicity of the peptides were also assessed. Our results identified several promising peptide inhibitors with high affinity for the Omicron RBD domain. These peptides exhibited strong hydrophobic interactions and significant binding strengths. The findings suggest that these peptides could potentially inhibit viral fusion and pathogenicity, with P11 being the most potent inhibitor. [ABSTRACT FROM AUTHOR]