Identification of potential SARS-CoV-2 Nsp1 inhibitors from Piper sarmentosum Roxb. using molecular docking

Area of Science:

• Molecular Biology
• Virology
• Computational Chemistry

Background:

• The SARS-CoV-2 Nsp1 protein is crucial for viral pathogenicity, inhibiting host mRNA translation and immune response by binding to ribosomes.
• The N-terminal region of Nsp1 is essential for its function, with mutations weakening its inhibitory effects.

Purpose of the Study:

• To conduct in silico screening of plant compounds from Piper sarmentosum Roxb. against key residues in the Nsp1 N-terminal domain.
• To identify potential Nsp1 inhibitors with favorable druggability profiles.

Main Methods:

• In silico screening of 112 compounds from Piper sarmentosum Roxb. against five target residues (Glu36, Glu37, Arg99, Arg124, Lys125) in SARS-CoV-2 Nsp1.
• Druggability assessment and molecular interaction analysis (hydrophobic, hydrogen bonding, π-cation) of identified compounds.
• SwissADME analysis to evaluate pharmacokinetic properties and identify the lead inhibitor.

Main Results:

• Five compounds, including stigmasterol, N-feruloyltyramine, and beta-Sitosterol, were identified as potential Nsp1 inhibitors.
• N-feruloyltyramine demonstrated strong binding interactions and favorable druggability, making it the ideal candidate.
• Molecular dynamics simulations indicated that N-feruloyltyramine binding increases flexibility in Nsp1's N-terminal loop regions (residues 54-70), potentially impacting protein stability and function.

Conclusions:

• Piper sarmentosum Roxb. contains compounds with potential to inhibit SARS-CoV-2 Nsp1.
• N-feruloyltyramine is a promising Nsp1 inhibitor candidate for further investigation.
• The interaction mechanism suggests N-feruloyltyramine may destabilize Nsp1, offering a novel therapeutic strategy against SARS-CoV-2.