Network pharmacology and molecular docking of Fraxinus floribunda: validating ethnomedicinal applications in T2DM

The current study investigates the network pharmacology, molecular docking, and molecular dynamics (MD) simulation of Fraxinus floribunda Wall. (Oleaceae) to validate its ethnomedicinal applications in Type 2 Diabetes Mellitus (T2DM). Five major bioactive compounds were identified using IMPPAT and TCMSP databases, based on pharmacokinetic properties (OB > 20%, DL > 0.18). Target genes for these compounds were predicted using Swiss Target Prediction, focusing on human targets with a high confidence score. A protein-protein interaction (PPI) network was constructed using the STRING database, revealing significant interactions among 143 nodes and 1300 edges. Molecular docking analysis revealed strong binding affinities of quercetin (- 10.4 kcal/mol), tamarixetin (- 10.4 kcal/mol), and isorhamnetin (- 9.5 kcal/mol) with MMP9, forming hydrogen bonds with key residues such as ALA189, GLN227, and TYR248. Molecular dynamics (MD) simulations confirmed the stability of the quercetin-MMP9 and tamarixetin-MMP9 complexes, with low RMSD values (~ 0.151 nm). Further, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations revealed favorable binding free energies, with quercetin exhibiting the highest binding affinity (- 6.82 kJ/mol), followed by tamarixetin (4.60 kJ/mol) and isorhamnetin (10.16 kJ/mol), reinforcing their potential role as MMP9 inhibitors. The findings highlight the potential of F. floribunda's bioactive compounds in managing T2DM, bridging traditional medicinal knowledge with modern computational tools to accelerate drug discovery and development. This integrative approach underscores the multifaceted pharmacological properties of F. floribunda, including antioxidant, anti-inflammatory, and potentially anti-obesity effects, aligning with broader health benefits beyond diabetes management. Further research and clinical validation are warranted to harness these natural compounds effectively for therapeutic development against T2DM and related metabolic disorders.

The online version contains supplementary material available at 10.1007/s40203-025-00348-y.