Elsevier

Microbial Pathogenesis

Volume 170, September 2022, 105701
Microbial Pathogenesis

Discovery of natural products to block SARS-CoV-2 S-protein interaction with Neuropilin-1 receptor: A molecular dynamics simulation approach

https://doi.org/10.1016/j.micpath.2022.105701Get rights and content

Highlights

  • Neuropilin-1 (NRP1) is a cell surface receptor protein interacting with the S-protein of the SARS-CoV-2 virus.

  • Furin-mediated proteolytic activity exposes the S1 protein C-terminal RRAR motif to the ligand-specific binding site of NRP1.

  • Therefore, blocking the S1-RRAR interactions with NRP1 with an antiviral drug would hinder virus infection of host cells.

  • Identifying natural compounds to block the RRAR-NRP1 complex are attractive therapeutic candidates for SARS-CoV-2 infection.

Abstract

Neuropilin-1 (NRP1) is a widely expressed cell surface receptor protein characterized by its pleiotropic function. Recent reports highlighted NRP1 as an additional entry point of the SARS-CoV-2 virus, enhancing viral infectivity by interacting with the S-protein of SARS-CoV-2. The ubiquitous distribution and mechanism of action of NRP1 enable the SARS-CoV-2 virus to attack multiple organs in the body simultaneously. Therefore, blocking NRP1 is a potential therapeutic approach against SARS-CoV-2 infection. The current study screened the South African natural compounds database (SANCDB) for molecules that can disrupt the SARS-CoV-2 S protein-NRP1 interaction as a potential antiviral target for SARS-CoV-2 cellular entry. Following excessive screening and validation analysis 3-O-Methylquercetin and Esculetin were identified as potential compounds to disrupt the S-protein-NRP1 interaction. Furthermore, to understand the conformational stability and dynamic features between NRP1 interaction with the selected natural products, we performed 200 ns molecular dynamics (MD) simulations. In addition, molecular mechanics-generalized Born surface area (MM/GBSA) was utilized to calculate the free binding energies of the natural products interacting with NRP1. 3-O-methylquercetin showed an inhibitory effect with binding energies ΔG of −25.52 ± 0.04 kcal/mol to NRP1, indicating the possible disruption of the NRP1-S-protein interaction. Our analysis demonstrated that 3-O-methylquercetin presents a potential antiviral compound against SARS-CoV-2 infectivity. These results set the path for future functional in-vitro and in-vivo studies in SARS-CoV-2 research.

Keywords

Virtual screening
SARS-CoV-2
S-Protein
Neuropilin-1
Natural product
Molecular dynamic simulation

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1

These authors contributed equally to this work.

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