Identification of polyphenols as novel neuropilin-1 cendR pocket inhibitors to block SARS-CoV-2 entry and enhance variant resistance.

Neuropilin-1 (NRP-1) functions as an essential co-receptor for SARS-CoV-2, facilitating viral entry by binding the spike protein's C-end rule (CendR) motif in its b1 domain, yet it has received less attention than ACE2 in therapeutic development. This in silico study evaluates plant-derived polyphenols as potential selective inhibitors of the NRP-1 CendR pocket to disrupt SARS-CoV-2 engagement, addressing limitations of synthetic inhibitors like EG01377, which exhibit modest affinity (-5.83 kcal/mol) and potential off-target risks. High-throughput molecular docking of 10,000 phytochemicals using AutoDock Vina identified 10 polyphenols with binding affinities ranging from -9.87 to -6.63 kcal/mol, led by 6"-O-acetyldaidzin (-9.87 kcal/mol) and phloretin (-8.64 kcal/mol), forming stable hydrogen bonds and π-cation interactions with critical residues (e.g., THR-401, GLU-367 for 6"-O-acetyldaidzin; PRO-311, ILE-400 for phloretin), as visualized in Discovery Studio. Notably, four of the top inhibitors are isoflavonoid derivatives, highlighting a chemical class enrichment. Molecular dynamics simulations over 100 ns using Desmond indicated moderate complex stability (RMSD: 0.6-3.8 Å; RMSF <0.5 Å at binding site). ADMET-Tox profiling via SwissADME and ProTox-II revealed drug-like properties, including high gastrointestinal absorption (>70% for leads) and low toxicity (classes 4-5), though 6"-O-acetyldaidzin shows limited bioavailability due to its high H-bond acceptor count (10) and large size, suggesting need for formulation optimization. The NRP-1 b1 homology model, built with SWISS-MODEL, exhibited high fidelity (GMQE: 0.79; Ramachandran favored regions: 90.3%). This focused computational screening of polyphenols against NRP-1 complements prior studies and identifies candidates for experimental validation as potential SARS-CoV-2 inhibitors. Limitations include the in silico nature, and lack of membrane/sialic acid models, necessitating in vitro and in vivo testing against SARS-CoV-2 variants.

Copyright: © 2026 Ataya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.