Resorcinol Derivatives as Novel Aldose Reductase Inhibitors: In Silico and In Vitro Evaluation

Abstract

Background: The polyol pathway, an alternative way of carbohydrate metabolism, is activated by hyperglycemia. Aldose reductase (AR), the first and rate-limiting enzyme of the polyol pathway, is responsible for the reduction of glucose to sorbitol. Inhibiting the aldose reductase enzyme and reducing the polyol pathway is considered an effective method to prevent and postpone the onset of diabetic complications. Objective: Therefore, in this work, we investigate the inhibition effects of certain resorcinol derivatives and the positive control compound quercetin on the AR enzyme in vitro and in silico. These phenolic compounds, whose inhibitory effects on the AR enzyme were investigated, were also compared with known drugs in terms of their drug-like characteristics. Methods: Three methods were used to determine the inhibitory effects of resorcinol derivatives on recombinant human AR enzyme. After the in vitro inhibition effects were determined spectrophotometrically, the binding energy and binding modes were determined by molecular docking method. Finally, the MM-GBSA method was used to determine the free binding energies of the inhibitors for the AR enzyme. Results: 5-pentylresorcinol compound showed the strongest inhibition effect on recombinant human AR enzyme with an IC50 value of 9.90 μM. The IC50 values of resorcinol, 5-methylresorcinol, 4- ethylresorcinol, 4-hexylresorcinol, 2-methylresorcinol, and 2,5-dimethylresorcinol compounds were determined as 49.50 μM, 43.31 μM, 19.25 μM, 17.32 μM, 28.87 μM, 57.75 μM, respectively. Conclusion: The results of this research showed that resorcinol compounds are effective AR inhibitors. These findings are supported by molecular docking, molecular mechanics, and ADME investigations undertaken to corroborate the experimental in vitro results.