Integrating Network Pharmacology to Investigate the Mechanism of Ginsenoside Compound K Against Coronavirus

The persistent threat of coronaviruses to global health necessitates urgent development of broad-spectrum therapeutics with high efficacy and low toxicity. Among promising candidates, ginsenoside compound K (CK)-a bioactive metabolite derived from <i>Panax</i> ginseng-has emerged with preliminary evidence indicating its potential anticoronavirus activity. The study integrates network pharmacology, molecular docking, molecular dynamics simulation, and surface plasmon resonance validation. A total of 226 shared targets between CK and coronaviruses were identified. Functional enrichment analysis revealed CK's involvement in critical processes such as immune regulation and key pathways including PI3K-Akt signaling and Coronavirus disease-SARS-COV-2. Protein-protein interaction analysis pinpointed four core targets: EGFR, STAT3, HSP90AA1, and ESR1, with molecular docking and dynamics simulations confirming high-affinity binding between CK and all core targets-experimental validation for EGFR showed a dissociation constant of 5.67 μM. The results demonstrate that CK exerts anticoronavirus effects through multitarget regulation, employing a dual mechanism: inhibiting viral entry via EGFR and HSP90AA1 and suppressing cytokine storms through modulation of the STAT3/ESR1-PI3K-Akt axis. This synergistic action overcomes the limitation of single-target antivirals by concurrently mitigating infection and hyperinflammation. Importantly, this work identifies HSP90AA1 and ESR1 as novel anticoronaviral targets, offering a mechanistic foundation for developing CK-based broad-spectrum therapeutics against coronaviruses.