Synergistic antioxidant and antidiabetic activities of Tinospora cordifolia and Azadirachta indica extracts supported by in-silico molecular docking and ADMET evaluation

Background: Type 2 Diabetes mellitus is a chronic metabolic disorder which worsens by increased oxidative stress resulting in other diabetes associated complications. Tinospora cordifolia (TC) and Azadirachta indica (AI) are traditional medicinal plants that has been used for diabetes since ancient times, but their combined potential as a formulation has not been evaluated for the management of diabetes. Objectives: This study aimed to profile the phytochemical composition of 70% hydroethanolic extracts of TC and AI, assess their antioxidant and antidiabetic activity individually and in combination, and further substantiate their efficacy through in-silico molecular docking and ADMET evaluation of their key bioactive compounds, berberine and nimbolide. Methods: Hydroethanolic extracts of TC and AI were subjected to preliminary phytochemical screening, quantification of primary and secondary metabolites, and HPTLC profiling. Five combinations of TC:AI (1:1, 1:2, 2:1, 1:3, 3:1) were prepared and evaluated for antioxidant activity using DPPH, ABTS, and FRAP assays, and for antidiabetic potential using α-amylase, α-glucosidase, and PTP1B inhibition assays. IC_₅₀ values were calculated. In-silico studies were performed for berberine and nimbolide using AutoDock 4.2.6 against PPARγ, GLUT4, and IRS1. Drug-likeness and ADMET properties were predicted using SwissADME and pkCSM. Results: Phytochemical profiling confirmed the presence of alkaloids, polyphenols, flavonoids, and tannins. TC demonstrated stronger inherent antioxidant and antidiabetic activity than AI. Among combinations, 1:1 and 3:1 formulations showed the highest potency with IC₅₀ values comparable to standards. Molecular docking revealed strong binding affinities of berberine and nimbolide toward PPARγ, GLUT4, and IRS1, while ADMET prediction indicated acceptable pharmacokinetic behaviour and good drug-likeness. Conclusion: The TC:AI 1:1 formulation exhibited synergistic antioxidant and antidiabetic effects, supported by favorable in-silico interactions and pharmacokinetic profiles, highlighting its potential as a natural therapeutic option for T2DM management.