Network pharmacology, molecular docking and in vitro experimental validation to unveil antidiabetic mechanism of...

Areca catechu nut exhibits potential antidiabetic properties due to its bioactive compounds, including alkaloids, flavonoids, and phenolic compounds, which enhance insulin sensitivity and glucose uptake. However, the specific compounds responsible and their underlying mechanisms remain undefined. This study employed an integrated computational and experimental approach to elucidate the antidiabetic action of Areca catechu. Phytochemicals were retrieved from Dr. Duke's and IMPPAT databases, and molecular targets were predicted using SwissTargetPrediction, SEA Search Server, and Binding Database. Disease-associated targets were obtained from DisGeNet, GeneCards, and MalaCards databases. Network pharmacology analysis identified carbonic anhydrase II (CA-II) as a key therapeutic target. Molecular docking using BIOVIA Discovery Studio revealed -CDOCKER Interaction Energy of chrysophanic acid (64.20 kcal/mol), isorhamnetin (62.52 kcal/mol), quercetin (54.54 kcal/mol), and ferulic acid (52.13 kcal/mol) had stronger binding affinities for CA-II than the reference inhibitor, acetazolamide (36.80 kcal/mol). These compounds were quantified using LC-MS/MS in nut extract, and their CA-II inhibitory activity was assessed using an in vitro assay. Chrysophanic acid exhibited the highest inhibitory activity (IC₅₀ = 0.3125 ± 0.03 µM), demonstrating a potency 17.9-fold greater than the reference drug, acetazolamide. Additionally, 100ns molecular dynamics simulations confirmed the stability of chrysophanic acid-CA-II interactions. Taken together, these results suggest that CA-II inhibition is a potential mechanism for the antidiabetic effects of Areca catechu. They also identify key lead compounds for future development as antidiabetic agents.

The online version contains supplementary material available at 10.1007/s40203-025-00464-9.