Structural bases for the inhibition of aldose reductase by phenolic compounds

• Published in: Bioorganic & medicinal chemistry 2000-05, Vol.8 (5), p.1151-1158
• Main Authors: RASTELLI, G, ANTOLINI, L, BENVENUTI, S, COSTANTINO, L
• Format: Article
• Language: English
• Subjects: Aldehyde Reductase - antagonists & inhibitors; Aldehyde Reductase - chemistry; Aldehyde Reductase - metabolism; Binding Sites; Biological and medical sciences; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; General and cellular metabolism. Vitamins; Hydrogen-Ion Concentration; Medical sciences; Molecular Conformation; Pharmacology. Drug treatments; Phenols - chemistry; Phenols - metabolism; Phenols - pharmacology; X-Ray Diffraction
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(00)00052-3

Aldose reductase (ALR2) is an enzyme involved in the development of long-term diabetic complications. In the search for aldose reductase inhibitors less acidic than carboxylic acids, phenolic compounds related to benzopyran-4-one and chalcone are particularly interesting because they possess good inhibitory properties. In order to investigate the similarities between these two classes of compounds and to provide a structural basis for their inhibition of ALR2, the existing structure-activity relationships were reconsidered. To this end, the acidity constants of a set of chalcones were measured and compared with those of benzopyran-4-one derivatives. Then, having established the relevant protonation state of these phenolics at physiological pH, a conformational analysis was performed on the most active benzopyran-4-one and chalcone derivatives and the results were compared with the crystal structures of some analogues. Finally, molecular docking of the most active chalcone into the ALR2 binding site was performed, and the structure of the enzyme-inhibitor complex was compared with that of the complex formed between ALR2 and a previously-obtained benzopyran-4-one derivative.