Adenocarpine, Marmesin, and Lycocernuine from Ficus benjamina as Promising Inhibitors of Aldose Reductase in Diabetes: A Bioinformatics-Guided Approach.

Abstract

Diabetes affects approximately 422 million people worldwide, leading to 1.5 million deaths annually and causing severe complications such as kidney failure, neuropathy, and cardiovascular disease. Aldose reductase (AR), a key enzyme in the polyol pathway, is an important therapeutic target for managing these complications. The high cost, severe side effects, and rising drug resistance in traditional diabetes treatments underscore the urgent need for novel AR-targeting antidiabetic agents. Ficus benjamina used in traditional medicine demonstrates promising potential for diabetes management. This study investigated the antidiabetic potential of F. benjamina phytocompounds targeting AR receptor employing a structure-based drug design approach to identify potential antidiabetic drug agents. Using molecular docking, ADMET analysis, molecular dynamics (MD) simulation, MM/GBSA, MM/PBSA, and DFT calculations, we identified three promising lead compounds: adenocarpine (- 9.2 kcal/mol), marmesin (- 8.8 kcal/mol), and lycocernuine (- 8.4 kcal/mol). These compounds presented favorable pharmacokinetic, pharmacodynamic, and toxicity profiles, with a 500-ns MD simulation confirming their stability, supported by PCA and Gibbs FEL analysis. MM/GBSA study identified adenocarpine (- 72.53 kcal/mol) as the best compound, outperforming marmesin (- 70 kcal/mol) and lycocernuine (- 61.95 kcal/mol). DFT analysis revealed that adenocarpine exhibited the highest molecular reactivity (3.914 eV), while lycocernuine demonstrated the greatest kinetic stability (6.377 eV). Marmesin and lycocernuine showed increased reactivity upon transitioning from the free states (4.441 eV and 6.377 eV, respectively) to the bound states (4.359 eV and 6.231 eV, respectively). These results could lead to the development of adenocarpine, marmesin, and lycocernuine as novel drug candidates for diabetes, warranting further in vitro and in vivo validation.