Synergistic Potential of Berberine and Metformin: Unlocking Enhanced Anti-Diabetic Efficacy.

Gestational diabetes mellitus (GDM) is a complex metabolic disorder characterized by glucose intolerance during pregnancy, posing significant health risks to both the mother and fetus. Current therapeutic options, including Metformin, show limitations, highlighting the need for novel, or adjunctive treatments to improve outcomes. This study aimed to identify novel and adjunctive phytocompounds with therapeutic potential against GDM using computational and experimental approaches. Text mining was employed to compile a phytochemical library, followed by molecular docking using AutoDock Vina against 17 GDM-associated targets. Drug-likeness, pharmacophore scoring, ADMET screening, molecular dynamics simulation, and in vitro studies were conducted to prioritize potent candidates. Berberine emerged as a promising anti-GDM compound based on docking scores, binding energies, and hydrogen bond interactions with GDM receptors. It achieved the highest pharmacophore selectivity score of 19.71 and met all drug-likeness criteria. Berberine demonstrated favorable renal excretion, high intestinal absorption (HIA) with 100% CaCO2 permeability, and acceptable blood-brain barrier (BBB) permeability. MD simulation revealed the high stability of Berberine. In vitro assays confirmed high glucose uptake (40.88 ± 0.51) and increased insulin secretion (129.78 ± 1.26) in the PANC-1 cell line in the Berberine-treated group as compared to the Metformin, revealing its superior anti-diabetic activity. Further, the group treated in combination of Berberine and Metformin showed the highest glucose uptake (50.63 ± 0.47) and insulin secretion (173.66 ± 1.78). The combined computational and experimental findings suggest that Berberine, a non-toxic phytochemical, holds potential as an effective therapeutic candidate for GDM. Its robust binding, high selectivity, enhanced activity and stability make it a promising lead compound for further development. Furthermore, the anti-diabetic effect is augmented when Berberine and Metformin are used together, indicating the synergistic potential of Berberine and Metformin in treating hyperglycaemic conditions like GDM.