Mechanistic basis of aldose reductase inhibition by phenolics from Achillea fragrantissima: experimental insights and computational validation.

Abstract

This study explores the inhibitory potential of phenolic compounds derived from Achillea fragrantissima against aldose reductase (AR), a key enzyme implicated in diabetic complications. Among the six tested compounds, salvianolic acid B exhibited the strongest inhibitory activity, with an IC₅₀ of 1.90 ± 0.1 µM, followed by chlorogenic acid (IC₅₀ = 3.79 ± 0.17 µM) and 3-caffeoyl-4-feruloylquinic acid (IC₅₀ = 4.49 ± 0.38 µM). The remaining three phenolics showed weak AR inhibition and were excluded from further analysis. Enzyme kinetics studies revealed that all three active compounds function as noncompetitive inhibitors, a finding further supported by in silico analyses. Molecular docking demonstrated strong binding affinities, with salvianolic acid B adopting the most favorable binding pose within the AR binding site. Molecular dynamics (MD) simulations confirmed the stability of AR-ligand complexes throughout the simulation period, while MM/PBSA calculations identified salvianolic acid B as having the lowest binding free energy, reinforcing its superior inhibitory potential. Additional validation through free-energy landscape (FEL) analysis and interaction energy profiling further substantiated the stability and efficacy of these inhibitors. Moreover, ADMET analysis indicated that all active compounds exhibit drug-like properties, with favorable bioavailability and gastrointestinal absorption. Overall, the in silico findings align with experimental results, underscoring the therapeutic potential of these phenolic compounds as AR inhibitors. These insights has the potential of the development for therapeutics for diabetic complications.

Supplementary information: The online version contains supplementary material available at 10.1007/s13205-025-04486-0.