Design And in Silico Screening of Thiazolidine-2,4-Dione Analogs as Potential Aldose Reductase Inhibitors

Defective insulin secretion and resistance to insulin action leads to diabetes mellitus. The oral hypoglycemic agents, such as thiazolidinediones (PPARγagonists) attenuate insulin resistance. Despite the use of well-planned dosage regimens of oral hypoglycemic agents/insulin or both, the prevention and control of this pathological condition is still a challenging task. There are numerous thiazolidinediones available in the chemical space which are still not explored for their therapeutic efficacy. Implementation of rational approaches makes the drug discovery process more goal-oriented and saves resources in terms of time and money. By considering the ongoing research on Aldose reductase inhibitors as antidiabetic agents, fifty thiazolidine-2,4-dione analogs (1-50) were designed to investigate their in silico drug-likeness profile and in silico binding pattern with Aldose reductase inhibitor receptor. Online tools, such as molinspiration and SwissADME were utilized to calculate drug-likeness properties of the designed compounds. All the compounds were found to obey the Lipinski Rule of Five and some of them have shown violations, indicating their good oral absorption. Calculation of synthetic accessibility score and bioavailability score of the selected compounds enabled us to understand the structure complexity, feasibility in their synthesis and their predicted bioavailability. Docking studies of ligands 1-50 was performed by using 1PWM,1PWL as target protein (Aldose reductase inhibitor isoform) and marketed thiazolidine-2,4-dione analogue, Fidarestat , Minalrestat respectively as a reference compound. The results indicated that interaction of ligand with key amino acid residues, TRP20, TYR48, HIS110, TRP111, LEU300 was important as they were observed in the docking analysis of reference Fidarestat, Minalrestat. The binding pattern of compounds 8, 14 and 15 were found to be similar to Fidarestat, Minalrestat. Thus, the outcomes of the study demonstrated the in-silico potential of above mentioned compounds as Aldose reductase inhibitors.