Targeting insulin signaling and TRAF2/JNK pathway: a comprehensive in silico study of Uncaria tomentosa compounds

Type 2 diabetes (T2D) is a metabolic syndrome frequently associated with obesity and endoplasmic reticulum stress-mediated inflammation, which can lead to unfolded protein response (UPR), impaired insulin signaling, and apoptosis. In an attempt to identify potential natural therapeutic candidates, this study investigated the mechanisms of action of fourteen compounds present in Uncaria tomentosa (UT), a medicinal plant from the Amazon rainforest, using in silico modeling. The study focused on UPR, TRAF2/JNK pro-inflammatory and insulin signaling pathways, which play key roles in T2D. The UT compounds were docked against several human proteins involved in these pathways, and molecular dynamics simulations confirmed stable interactions between the target proteins (PERK, TRAF2, JNK, TNF-α, IRS-1, PI3K, AKT, GSK3β, and PPARγ) and four of the UT compounds, 5-Carboxystrictosidine , Cinchonain , Epicatechin and Mitraphylline . Additionally, ADMET property analyses were conducted for the four promising compounds, revealing favorable pharmacokinetic properties. These findings suggest that specific UT compounds may offer therapeutic potential in managing T2D by modulating signaling pathways related to the conditions UPR, inflammation, and insulin resistance.