Polyherbal DPP-IV inhibitors: In silico and in vivo insights into anti-diabetic drug design

Dipeptidyl peptidase-IV (DPP-IV) inhibition is an established therapeutic strategy for diabetes management by prolonging incretin activity. Though individual medicinal plants have shown antidiabetic potential, systematic evaluation of polyherbal formulations (PHFs) constituting of multiple phytochemicals remains limited. This study is the first to systematically evaluate the DPP-IV inhibitory potential and multi-organ protective effects of a polyherbal formulation (PHF) composed of extracts of Gymnema sylvestre, Berberis aristata, Cassia fistula, Withania coagulans, and Syzygium cumini, through a combined approach of in silico molecular docking, ADMET profiling, and in vivo validation of the PHF in alloxan-induced diabetic rats. Phytoconstituents from the five medicinal plants were screened using Lipinski’s criteria, ADMET analysis, and molecular docking against DPP-IV (PDB ID: 5T4B). Further the efficacy of the PHF was evaluated in vivo using alloxan-induced diabetic Wistar rats treated with PHF (100 and 200 mg/kg) for 28 days. Blood glucose, HbA1c, lipid profile, hepatic and renal biomarkers were assessed to establish the antidiabetic property of the PHF. Withasomidienone exhibited the strongest DPP-IV binding affinity (–13.7 kcal/mol), lower than the reported inhibitor Vildagliptin (–10.28 kcal/mol), closely followed by β-Amyrin, lupeol, and Withacoagin. ADMET properties of these phytochemicals indicated favourable bioavailability and low toxicity. In vivo, PHF at 200 mg/kg significantly reduced fasting glucose, HbA1c, triglycerides, SGOT, SGPT, bilirubin, creatinine, and urea, while improving HDL levels and restoring renal functioning. The current experimental findings demonstrate that this novel polyherbal formulation exhibits multi-organ protective effects. The computational approach of the study supports the findings by indicating that potent DPP-IV inhibition property of the PHF might be primarily driven by the key phytochemical constituents such as Withasomidienone, β-amyrin, lupeol and others. The strong concordance between in silico predictions and in vivo outcomes suggests a synergistic effect of the phytochemicals in combating the diabetes induced pathophysiological processes. Schematic representation of the integrated in silico and in vivo evaluation of selected medicinal plants for antidiabetic activity. Phytochemicals were first screened through molecular docking against the DPP-IV enzyme, followed by experimental validation in animal models to assess hepatic, renal, and glycemic outcomes, demonstrating the overall antidiabetic effect mediated via DPP-IV inhibition.