Bioinformatics‐Integrated Molecular Docking and Molecular Dynamics Simulations for the Rational Design of Novel Aldose Reductase Inhibitors

ABSTRACT Aldose reductase is an essential enzyme in the polyol system, and its activation by hyperglycemic factors contributes to the formation of chronic diabetes problems, as well as an important activator of inflammatory and cytotoxic states even when blood glucose levels are normal. As a result, it provides a great therapeutic target, and significant research is underway to identify new molecules capable of inhibiting it. We have used a Breed‐based de novo hybridization method to identify new aldose reductase inhibitors in our study. The best hybridized breed compounds among all the created breed ligands were the developed inhibitors Breed 1, Breed 2, and Breed 3. Furthermore, the in silico pharmacokinetic calculations for these hybridized inhibitors fell within the specified range that is appropriate for human usage. Furthermore, a synthetic methodology for the identified molecules has been created. At the atomic level, MD simulations (100 ns) were carried out for every complex using the Gromacs program. The findings indicate that the suggested inhibitors form exceptionally stable complexes with the enzyme, in contrast to the clinical inhibitors. The outcomes of the free energy landscape (FEL), dynamic cross‐correlation matrix (DCCM), and molecular mechanics Poisson–Boltzmann surface area (MM‐PBSA) computations demonstrate that the designed inhibitors form very stable systems without altering the original configuration of aldose reductase.