Virtual screening of knottin and defensin peptides perceives hits against the SARS CoV-2 RBD domain and hACE2 interaction

18 January 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Targeting protein-protein interactions (PPIs) between the receptor binding domain (RBD) of SARS-CoV-2 and human angiotensin converting enzyme (ACE2) has been an attractive therapeutic target for peptide or protein drug discovery to inhibit the entry of SARS-CoV-2 into the host cells. Developing inhibitors for such extensive (RBD and human ACE2 interaction) contact surfaces involves multiple challenges. We sought to start in silico investigation with well-known knottins peptides from its databank for the first time and host defense peptides, defensins, due to their multifaceted antimicrobial activity. The molecular-level examination resulted in a handful of peptides binding selectively with the spike glycoprotein at low nanomolar potency. They exhibited a high thermodynamic binding stability in an MD simulation study. Noteworthy, Kalata B1 and human β-defensin 4 (HBD4) showed excellent interaction parameters calculated through an alanine scan of hot spot residues. These natural source peptide inhibitors could be a promising lead for developing SARS-CoV-2 prophylactic after an ongoing experimental assay test.


Human Angiotensin-Converting Enzyme 2 (hACE2)
peptide inhibitors
protein-protein interactions
Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA)

Supplementary materials

The natural remedy for COVID19 treatment may arrive soon
African plant Oldenlandia affinis tea could emerge as potential herbal medicine for COVID19 treatment. In parral, our host defense antimicrobial peptides are highly promising agents for COVID treatment.


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