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. This in silico study evaluates plant-derived polyphenols as potential selective inhibitors of the NRP-1 CendR pocket. High-throughput molecular docking of 10,000 phytochemicals identified 10 polyphenols with high binding affinities, led by 6"-O-acetyldaidzin and phloretin. Molecular dynamics simulations indicated moderate complex stability, and ADMET-Tox profiling revealed drug-like properties with low toxicity. The findings suggest these candidates could disrupt SARS-CoV-2 infectivity and complement existing ACE2-targeted therapies.