A ricin-based peptide BRIP from Hordeum vulgare inhibits Mpro of SARS-CoV-2

Abstract

COVID-19 pandemic caused by SARS-CoV-2 led to the research aiming to find the inhibitors of this virus. Towards this world problem, an attempt was made to identify SARS-CoV-2 main protease (Mpro) inhibitory peptides from ricin domains. The ricin-based peptide from barley (BRIP) was able to inhibit Mpro in vitro with an IC50 of 0.52 nM. Its low and no cytotoxicity upto 50 µM suggested its therapeutic potential against SARS-CoV-2. The most favorable binding site on Mpro was identified by molecular docking and steered molecular dynamics (MD) simulations. The Mpro-BRIP interactions were further investigated by evaluating the trajectories for microsecond timescale MD simulations. The structural parameters of Mpro-BRIP complex were stable, and the presence of oppositely charged surfaces on the binding interface of BRIP and Mpro complex further contributed to the overall stability of the protein-peptide complex. Among the components of thermodynamic binding free energy, Van der Waals and electrostatic contributions were most favorable for complex formation. Our findings provide novel insight into the area of inhibitor development against COVID-19.

Inhibition of nonstructural protein 15 of SARS‐CoV‐2 by golden spice: A computational insight

“…The generated trajectory holds all dynamical data required for calculating several features. The RMSD of the protein backbone calculated from the MD simulations illustrated the stability of the protein‐ligand complexes 37,38 . Every amino acid residue related to the protein‐ligand complex was accountable for the endurance of the dynamic conformity.…”

“…For more validation, MD simulations were carried out using the MD simulations illustrated the stability of the protein-ligand complexes. 37,38 Every amino acid residue related to the proteinligand complex was accountable for the endurance of the dynamic conformity. The fluctuation of any selective amino acid regarding the native structure can be estimated by the RMSF parameter determined from the MD simulation trajectories.…”

L-shaped distribution of the relative substitution rate (c/μ) observed for SARS-COV-2's genome, inconsistent with the selectionist theory, the neutral theory and the nearly neutral theory but a near-neutral balanced selection theory: Implication on “neutralist-selectionist” debate

“…It is therefore critical to investigate the substitution rate variations in the SARS-CoV-2 genome for identifying key NT sites [ 35 , 36 ] and key genomic regions under positive selections. The key mutations and regions associated with high infection and virulence can be potential drug targets in treating COVID-19 [ [37] , [38] , [39] ].

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Dock-able linear and homodetic di, tri, tetra and pentapeptide library from canonical amino acids: SARS-CoV-2 Mpro as a case study

“…One molecule that has shown some activity is a peptidomimetic arising from a high-throughput screen of Ugi reaction products [35]. Although no natural peptide is likely to be a useful drug in itself [36], they might prove to be useful starting points for structure-activity relationships through both incorporating unnatural residues and modifying the backbone to increase the stability of the peptide (both physiologically and to avoid peptidase activity in the binding site) and affinity for the target [37]. But for this to be viable, we require a method to identify promising peptides to be validated in vitro as potential inhibitors.…”