Chronic diabetes problems arise from the activation of aldose reductase (AR), the primary enzyme of the polyol pathway, under hyperglycemic circumstances. The spirooxindole ring system comes out to be a fascinating class of naturally occurring compounds with pharmaceutical interest. In this work, we have chosen three dispirooxindolopyrrolizidines (DSOIP-H, DSOIP-Me, and DSOIP-OMe) to investigate their ability to inhibit AR. Through molecular docking studies, the order of binding energy was calculated as DSOIP-H (-8.23 kcal/mol) < DSOIP-Me (-8.58 kcal/mol) < DSOIP-OMe (-8.72 kcal/mol). The three ligands showed effective binding with AR's catalytic active site through hydrophobic interactions. The ADME analysis revealed valuable insights into the ligands' pharmacokinetic properties. Through protein-ligand interactions, DSOIP-OMe consistently interacted with the amino acid residues of the AR enzyme's active site areas, as demonstrated by the molecular dynamic (MD) trajectory analysis. The exceptional inhibitory efficacy of DSOIP-OMe has been established based on its binding energy values of -92.69 kJ/mol as determined by MM-PBSA. The PHE122 residue of AR is recognized as a crucial residue that made a substantial contribution to the binding energy of MM-PBSA through hydrophobic interactions.
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