Development of AKR1B10 inhibitors from Ajuga nipponensis based on diseases and targets

Ten compounds (1−10) including one new neoclerodane diterpenoid (1) and nine known compounds were isolated from the whole plants of Ajuga nipponensis. Their structures were established by performing detailed analysis of NMR, the structure of 1 was determined using HRESIMS, 1D and 2D NMR, UV, and IR. Compounds 1 and 4–10 were isolated from Ajuga nipponensis for the first time. And it was the first time to report compounds 9 and 10 as natural products. Based on network pharmacology methods, 45 key targets were selected, which were compounds mapping to diseases. And compounds 2, 3, 7, and a (ajugacumbin B) exhibited excellent AKR1B10 inhibitory activities, with IC50 values of 53.05 ± 0.75, 87.22 ± 0.85, 61.85 ± 0.66, and 85.19±1.02 nM respectively, with Epalrestat used as the positive control (82.09 ± 1.62 nM). Additionally, the interaction between active compounds and AKR1B10 had been discussed according to the molecular docking results. Ultimately, the analysis of GO and KEGG enrichment indicated that the key signaling pathway of the active compounds may be related to prostate cancer. Our study results demonstrate the hypoglycemic and anti-tumor properties of A. nipponensis for the first time, and provide a comprehensive understanding of its application in traditional medicine. Furthermore, this article establishes a reference for further research on the optimized experimental design of novel AKR1B10 inhibitors.