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

Abstract

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.

Computational Exploration of Berberis lycium Royle: A Hidden Treasure Trove for Antiviral Development

“…In this graph, the simulation duration is shown against the RMSD of the protein backbone, which is computed for each time step. 75 , 76 …”