Computational Bioprospection of Selected South African Essential Oils for Inhibition of Aldose Reductase and Sorbitol Dehydrogenase for Diabetes Therapy

Abstract This study investigates metabolites from South African essential oils ( Agathosma betulina , Cymbopogon citratus, Artemisia afra) as inhibitors of aldose reductase (AR) and sorbitol dehydrogenase (SDH), key enzymes involved in diabetic complications. MMGBSA analysis identified quercetin‐7‐O‐glucoside (Q7G) as a potential dual inhibitor of AR (ΔGbind: −51.80 kcal/mol) and SDH (ΔGbind: −34.41 kcal/mol), and quercetin‐3,7‐diglucoside (Q37DG) also demonstrated potent SDH inhibition (ΔGbind: −70.52 kcal/mol), surpassing epalrestat (ΔGbind: −30.55 kcal/mol). 120 ns post‐dynamic simulation confirmed increased enzyme‐compound stability, with RMSD of 1.39–1.48 Å versus AR‐apo (1.56 Å) and 2.48–2.86 Å versus SDH‐apo (2.95 Å). These compounds stabilize enzyme structures through hydrogen bonding and π‐π interactions with catalytic residues. A strong correlation (0.5 ≤ |r| ≤ 0.95) between maximum electrostatic potential, polarizability, LUMO, and binding free energy indicates electrostatic interactions as primary determinants in compound‐AR/SDH binding. Pharmacokinetic analyses showed minimal blood‐brain barrier penetration and no significant inhibition of CYP450 enzymes, suggesting a lower risk of CNS adverse effects and drug interactions. These phytochemicals, especially Q7G, are potential leads in preventing diabetic complications such as retinopathy by regulating the polyol pathway through inhibition of AR and SDH. Further investigation into experimental efficacy and targeted drug delivery for Q7G and Q37DG is recommended.