Computational discovery of curcumin 4'-O-β-D-gentiobioside as a dual anti-virulence and anti-cancer agent

Despite the established epidemiological synergy between Porphyromonas gingivalis-induced periodontitis and oral squamous cell carcinoma (OSCC), a critical gap remains in developing single-agent therapeutics that simultaneously neutralize bacterial virulence and suppress host oncogenic signaling. This study aimed to comprehensively evaluate Curcumin 4'-O-β-D-gentiobioside (COG) as a novel, dual-pathway phytochemical intervention targeting the keystone virulence factor RgpB while concurrently disrupting OSCC progression networks.

A multi-modal computational approach was used, including network pharmacology, molecular docking, molecular dynamics simulations, and ADMET profiling. Anti-aging activity was predicted through pharmacological activity modeling.

Network pharmacology identified Curcumin 4'-O-β-D-gentiobioside (COG; PubChem CID: 46926100) targeting hub genes (TNF, IL6, EGFR, AKT1), enriching immune regulation, apoptosis, and oxidative stress pathways (FDR < 0.05). Docking revealed strong binding to RgpB (XP GScore: - 9.867 kcal/mol), supported by hydrogen bonds and π-stacking. Molecular dynamics confirmed stability (RMSD: 1.0-1.5 Å; ΔG =  - 14 kcal/mol). COG downregulated pro-inflammatory (CXCL10, MAPK8) and oncogenic (MDM2, BCL2L1) mediators, while enhancing ER stress response (KDELC1, ATF4). ADMET analysis predicted high absorption, negligible neurotoxicity, and no hepatotoxicity/genotoxicity. Predicted anti-aging activities included senolytic, antioxidant, and NF-κB inhibition.

These results position COG as a promising dual-agent that concurrently neutralizes RgpB virulence, disrupts chronic inflammation, and suppresses OSCC progression, addressing a critical unmet need in oral disease therapeutics. These findings warrant in vivo validation for translation into oral disease therapeutics.