Study of Pineapple Bioactive Compounds Targeting Aldose Reductase: A Natural Intervention for Diabetes Mellitus Pathologies.

Aldose reductase is a reduced monomeric enzyme that utilizes NADPH as a cofactor to mediate the glucose reduction to sorbitol in the polyol pathway. Overexpression of aldose reductase has been observed to mediate pathologies associated with diabetes mellitus. Inhibition of aldose reductase thus seems promising to deal with these pathologies. Pineapple and its extract have been identified for its anti-diabetic effect due to the presence of effective bioactive agents. In the present study, the major bioactive compounds of pineapple have been studied for their potential to structurally inhibit aldose reductase. The ADMET analysis of lead bioactive compounds including myrcene, palmitic acid, limonene, n-decanal, beta-carophyllene, 1-cyclohexane-1-caboxaldehyde, and α-farnesene showed most of the compounds were non-toxic and have druglike properties with LD50 values of greater than 2000 mg/kg. Molecular docking of these compounds at the substrate binding site of the aldose reductase-NADPH complex disclosed effective binding with binding energy values of - 5.025 to - 8.003 kcal/mol. α-farnesene, known for its antibacterial, antiviral, and anti-inflammatory properties gave the highest binding energy of - 8.003 kcal/mol. The molecular dynamic simulation studies of α-farnesene-aldose reductase-NADPH ternary complex, aldose reductase-NADPH binary complex, and apo-aldose reductase revealed similar RMSD values with respect to time during the simulation trajectory indicating stable interaction of the compound with the enzyme. DFT analysis showed high reactivity of α-farnesene which favours its utilization as a drug for specific target protein. Therefore, this study provides an efficient natural aldose reductase inhibitor α-farnesene that can be further explored for its potential to develop an effective natural drug to treat diabetes.