Unveiling the molecular interactions of flavonoid derivatives as human aldose reductase inhibitors: a detailed DFT-based per-residue interaction energy mapping.

Human aldose reductase (AR) is the enzyme that determines the rate of the polyol pathway and is an important therapeutic target for preventing complications arising from diabetes over a long period of time. Although numerous flavonoid derivatives can be used as AR inhibitors, understanding the interactions between ligands and critical amino acids at the binding site at the quantum mechanical level is of great importance for computational drug design. In this study, the interaction energies of 46 flavonoids, which are known to experimentally bind to the active site of the human aldose reductase (hAR) enzyme, with the amino acids in their binding pocket were calculated using DFT-based per-residue methodology. Following molecular docking procedures, the energies of the interactions between the amino acids in the binding site and the docked ligands were calculated at the M06-2X/6-31G(d,p) level of theory. To facilitate the analyses, these 46 compounds were divided into 6 groups, from those showing high activity to those showing low activity, based on their biological activity values. The interaction energies and amino acid/ligand contact numbers obtained from the calculations were visualized using both tables and clustered bar graphs. The results reveal that Trp20, Trp111, and Tyr48 are critical amino acids capable of forming consistent interactions with the vast majority of ligands. Clustered bar graphs clearly illustrate the repulsive and attractive interactions that occur between ligands and amino acids, as well as the number of contacts between them. This study focuses on mapping the energy profile at the electronic level rather than qualitatively observing the binding process. It also provides a detailed quantitative map of the AR enzyme's binding pocket. The identified critical amino acid residues and interactions provide a structural template for the design of next generation flavonoid derivatives.