Multi-target immunomodulatory actions of Elaeagnus rhamnoides L.) A. Nelson phytocompounds on immune regulatory targets via integrative network pharmacology, docking, and molecular simulation

Abstract

Introduction

Elaeagnus rhamnoides (sea buckthorn; 沙棘 Shāji) has long been valued in Chinese traditional medicine as fruit purees, decoctions, and polysaccharide granules for enhancing immunity, treating chronic cough, nourishing yin, and promoting digestive and cardiovascular health. However, the precise immunomodulatory mechanisms of its bioactive compounds remain inadequately understood.

Methods

This study comprehensively evaluated key phytocompounds from E. rhamnoides using network pharmacology and in silico computational analysis. Network pharmacology and molecular docking were applied to evaluate interactions with immune checkpoint proteins CTLA-4 (1AH1) and LAG-3 (7TZG). Electronic properties were assessed using density functional theory (DFT) calculations of HOMO–LUMO energy gaps. Molecular dynamics (MD) simulations and MM-GBSA analyses assessed protein–ligand stability and binding energies. ProTox-II toxicity profiling and network pharmacology further elucidated safety and biological pathway associations.

Results

All selected phytocompounds showed strong binding affinities with CTLA-4 and LAG-3, with narcissin, tellimagrandin I, and astragalin demonstrating the most favourable docking scores and molecular interactions. DFT analysis revealed low HOMO–LUMO gaps (3.76–4.82 eV) for strictinin and tellimagrandin I (high chemical reactivity) and higher kinetic stability for astragalin and narcissin. MD simulations confirmed the stability of astragalin complexes, and MM-GBSA revealed that hydrophobic packing and van der Waals forces were the primary drivers of binding affinity. ProTox-II predicted generally low risks of organ toxicity for all compounds. Network pharmacology showed these phytochemicals target multiple core immune-regulatory genes (including NFB1, HIF1A, MAOA, and TLR4) and are involved in critical immunological pathways such as NF-κB, cytokine signalling, and the PD-1/PD-L1 axis.

Discussion

This study provides the first comprehensive in silico systems pharmacology analysis of E. rhamnoides phytocompounds as multi-target, low-toxicity immunomodulators, supporting traditional Chinese medicine applications. The strong and stable binding to immune checkpoints, favorable electronic properties, and multi-pathway engagement reinforce their promise as plant-based immunotherapeutics. These findings support further experimental validation and recommend the featured E. rhamnoides phytocompounds as promising multi-target leads for the development of novel immunomodulatory therapeutics in modern and traditional Chinese medicine contexts.