Molecular Docking Study and Evaluation of the Anti‐diabetic Complications of Dihydroxanthyletin‐type Coumarins from Angelica decursiva
Authors: JUNG HYUN AH , Ali Md Yousof , Jannat Susoma , Park Seul Ki , Choi Jae Sue 
Published: November 2023

Diabetes is a very common disease that has assumed epidemic proportions, affecting 5.9% of the worldwide adult population. As the disease develops, a parallel increase has been seen in the prevalence of complications like cataract, nephropathy, retinopathy, neuropathy, and heart diseases. Various mechanistic explanations have been proposed as the cause of these complications, where the formation of advanced glycation end products (AGE) and the aldose reductase (AR)‐related polyol pathway are generally accepted mechanisms, which represent potential targets for the treatment of these complications. Angelica decursiva Fr. et Sav is a perennial herb that is widely distributed in China, Japan, and Korea. This plant has been long been used in traditional Korean medicine as an antitussive, analgesic, antipyretic, and cough remedy. In traditional Chinese medicine, it is used as a remedy for thick phlegm, asthma, and upper respiratory tract infections. The plant is a rich source of different coumarins, which have been reported to possess a wide range of biological activities, including anti‐inflammatory, antioxidant, and anti‐diabetic activities. Recently, we reported the potential anti‐diabetic activity of MeOH extracts and their constituents through the inhibition of protein tyrosine phosphatase 1B and α‐glucosidase. However, no detailed investigations are available on the major constituents of dihydroxanthyletin‐type coumarins from A. decursiva regarding the possibility of developing anti‐diabetic complications drugs. Therefore, we investigated the anti‐diabetic complications potential of seven natural dihydroxanthyletin‐type coumarins, 4‐hydroxy Pd‐C‐III (1), 4′‐methoxy Pd‐C‐I (2), Pd‐C‐I (3), Pd‐C‐II (4), Pd‐C‐III (5), decursidin (6), and (+)‐trans‐decursidinol (7) isolated from Angelica decursiva and evaluated their inhibitory activities against AGE formation and human recombinant aldose reductase (HRAR) activity. Coumarins 1–7 exhibited dose‐dependent inhibitory activities on AGE and HRAR with IC50 values ranging of 0.41–5.56 μM and 1.03–21.31 μM, respectively. Kinetic analysis of HRAR inhibition showed that 1, 3, 4, and 7 were competitive‐type inhibitors, 6 was a mixed‐type inhibitor, whereas 2 and 5 were noncompetitive‐type inhibitors. To further understand the mechanisms of action of the coumarins with inhibitory activity against HRAR with coumarins 1–7, we performed molecular docking simulations using AutoDock Vina. As a result, the simulated enzyme‐inhibitor complexes exhibited negative binding energies (Autodock Vina = −9.6 to −8.1 kcal/mol for HRAR), indicating a high affinity and tight binding capacity for the HRAR active site. In conclusion, these results suggest that the dihydroxanthyletin‐type coumarins from A. decursiva are potential major compounds that can be used in the prevention and/or treatment of diabetic complications.Support or Funding InformationThis research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) and funded by the Ministry of Science, ICT, & Future Planning (2014R1A1A3051684).