Integrated metabolomics and computational pharmacology to reveal the complementary antidiabetic mechanisms of...

Type 1 diabetes mellitus is a complex metabolic disease that involves various physiological mechanisms. Tithonia diversifolia, Curcuma longa, and Moringa oleifera (TCM) have been proposed as promising antidiabetic plants; however, their combined mechanistic potential remains unclear. This study aimed to identify the active compounds and explore the complementary pharmacodynamic and pharmacokinetic mechanisms of the TCM polyherbal formulation as a potential antidiabetic agent. The active constituents of TCM polyherbal formulations were characterized using liquid chromatography-high resolution mass spectrometry (LC-HRMS), followed by in silico ADME analysis, network pharmacology, molecular docking, and molecular dynamics simulations. LC-HRMS analysis identified several candidate bioactive compounds, including tagitinin A, quinic acid, and curcuminoids. Drug-likeness screening yielded 23 compounds that met the predefined criteria. These compounds exhibited potentially complementary pharmacokinetic effects by inhibiting the P-glycoprotein and cytochrome P450 enzymes. Network pharmacology analysis reduced 13,419 diabetes-related proteins to 21 prioritized hub targets collectively involved in inflammation, oxidative stress, and insulin regulation. Docking and molecular dynamics simulations demonstrated stable binding of key TCM constituents (tagitinin A, nootkatone, bisdemethoxycurcumin, demethoxycurcumin, and curcumin) to critical inflammatory mediators (TNF-α, COX2, iNOS, MAPK14, MAPK8), an oxidative stress-related enzyme (PARP1), and an incretin-regulating protease (DPP4). These findings suggest that the active compounds in TCM polyherbal may exert complementary pharmacokinetic and pharmacodynamic effects against type 1 diabetes, providing a comprehensive theoretical framework for future in vitro and in vivo validation.