Effects and molecular mechanisms of the combination of <i>Andrographis paniculata</i> and <i>Anredera cordifolia</i> as an insulin sensitizer: <i>in vitro</i> , network pharmacology, molecular docking, and dynamics studies

Due to the complex mechanism of insulin resistance (IR), multi-component herbal medicines might be an alternative approach in the treatment of IR-related diseases, such as type 2 diabetes mellitus (T2DM). <i>Andrographis paniculata</i> (AP) and <i>Anredera cordifolia</i> (AC) have been reported to have anti-diabetic effects. However, their effect and mechanism of action in a mixed formula (FAPAC), especially as an insulin sensitizer have not been reported. Therefore, <i>in vitro</i> studies were performed to investigate the effect of FAPAC, and the molecular mechanisms were predicted by in silico studies through network pharmacology, molecular docking, and dynamics simulations. <i>In vitro</i> studies demonstrated that FAPAC at 2 µg/mL was comparable to metformin in increasing glucose uptake in IR-HepG2 cells. KEGG analysis revealed that IR was the top pathway and predicted that FAPAC acts as an insulin-sensitizing agent by inhibiting three main targets: IKBKB, PRKCD, and PTPN1. Consensus docking suggested 7-O-methyl wogonin, ninandrographolide, and 3-O-β-D-glucopyranosyl andrographolide as the potent inhibitors for IKBKB, PRKCD, and PTPN1, respectively. Furthermore, molecular dynamics confirmed that the potential compounds remained in the binding pocket throughout the simulation and had a good affinity toward their respective targets, comparable to native ligands.