Over
50 peptides, which were known to inhibit SARS-CoV-1, were
computationally screened against the receptor-binding domain (RBD)
of the spike protein of SARS-CoV-2. Based on the binding affinity
and interaction, 15 peptides were selected, which showed higher affinity
compared to the α-helix of the human ACE2 receptor. Molecular
dynamics simulation demonstrated that two peptides, S2P25 and S2P26,
were the most promising candidates, which could potentially block
the entry of SARS-CoV-2. Tyr489 and Tyr505 residues present in the
“finger-like” projections of the RBD were found to be
critical for peptide interaction. Hydrogen bonding and hydrophobic
interactions played important roles in prompting peptide–protein
binding and interaction. Structure–activity relationship indicated
that peptides containing aromatic (Tyr and Phe), nonpolar (Pro, Gly,
Leu, and Ala), and polar (Asn, Gln, and Cys) residues were the most
significant contributors. These findings can facilitate the rational
design of selective peptide inhibitors targeting the spike protein
of SARS-CoV-2.