Ginsenoside Rb1 as a multi-target modulator in heart failure: Mechanistic insights into extracellular remodeling and transcriptional pathways from network pharmacology, molecular dynamics, and binding free energy analyses.

BACKGROUND

Heart failure is a leading global health burden, often driven by Angiotensin II (Ang II)-induced processes such as inflammation, fibrosis, and extracellular matrix remodeling. These mechanisms involve multiple protein hubs, making single-target drugs insufficient. Natural products such as Ginsenoside Rb1, a major bioactive constituent of Panax ginseng, have emerged as promising multi-target agents, though their mechanistic roles in cardiovascular protection remain incompletely defined.

METHODS

A combined strategy of network pharmacology, protein-protein interaction analysis, molecular docking, molecular dynamics (MD) simulations, and MM/GBSA binding free energy calculations was employed. Hub proteins associated with Ang II-mediated heart failure were identified, followed by docking and MM/GBSA analyses to compare the binding affinity of Rb1 against reference drugs (Losartan, Enalapril, and Carvedilol). Protein-ligand interaction maps, hydrophobicity profiling, and electrostatic potential (ESP) analyses were used to elucidate binding mechanisms.

RESULTS

Five hub proteins-MMP9, FN1, JUN, FGF2, and STAT3-were identified as central to Ang II-driven remodeling, inflammation, and transcriptional regulation. MM/GBSA analyses revealed consistently favorable ΔGbind values for Rb1, including -36.40 kcal/mol (FN1), -35.30 kcal/mol (STAT3), and -33.70 kcal/mol (JUN), which were comparable to or exceeded those of the reference drugs. In contrast, Rb1 showed moderate affinity at MMP9 (-31.80 kcal/mol) and FGF2 (-30.70 kcal/mol). Interaction plots demonstrated that the amphipathic nature of Rb1, with a bulky hydrophobic backbone and multiple polar hydroxyl groups, enabled multidentate hydrogen bonding, van der Waals stabilization, and π-alkyl interactions across diverse binding pockets. Hydrophobicity and ESP mapping further confirmed that Rb1 adapts effectively to both hydrophobic and polar microenvironments, explaining its broader multi-target binding capacity compared to the more structurally restricted reference drugs.

CONCLUSION

This study highlights Ginsenoside Rb1 as a promising polypharmacological candidate for heart failure, showing strong and adaptable binding to multiple Ang II-related targets.