Evaluation performance of FDA approved drug candidates as Aldose Reductase enzyme inhibitors by in silico drug repurposing and subsequent in vitro experimental study as therapeutic strategy for preventing and treating diabetic complications

Diabetes mellitus means a group of metabolic diseases in which blood glucose levels remain abnormally high. High-levels of blood sugar that persist in diabetes may bring forth significant health hazards from damage to small blood vessels resulting in conditions such as retinopathy, neuropathy, and nephropathy, and matters of bigger blood vessels such as cardiovascular disease. An important mechanism for these problems, especially those related to nerves, eyes, and kidneys, is increased citrate activity of aldose reductase accompanying elevated blood sugar levels. This brings about activation of the polyol pathway, which increases the oxidative stress of the body and thus participates in the tissue damage very often seen with chronic diabetes.First this study used molecular docking to choose lead compounds that might interact with aldose reductase ar and then used md simulations to study how the chosen candidates interact with the protein it was also confirmed by using different in vitro diagnostic strategies developing ar inhibitors that are safer and more effective could be an innovative way to help prevent complications that chronic diabetes can cause.Virtual screening with high-throughput was performed for all 1615 fda-approved drugs against the aldose reductase ar protein out of the initial pool 100 compounds demonstrated good bindings and were evaluated further using the xp docking method to better explore how the protein-ligand complexes interact and remain stable md simulations were performed over 100 nanoseconds next the drugs that showed promise were tested in the lab to check if they stopped the ar from functioning with the help of computers and experiments scientists sought out ar inhibitors that might be used in diabetes treatment to help manage its complications.Six compounds exhibited the best XP docking scores. Dapagliflozin showed the highest affinity towards AR (-17.2649 kcal/mol), followed by Latisse (-13.4748 kcal/mol), pioglitazone (-13.0546 kcal/mol), pitavastatin (-12.0516 kcal/mol), avanafil (-12.0251 kcal/mol), and viroptic (-11.9942 kcal/mol). MD simulations confirmed the stability of these compounds in the active site of AR. In vitro investigations showed that all lead compounds significantly inhibited AR, with dapagliflozin being the most potent (IC50 = 2.02 µg/ml), followed by Latisse (2.457 µg/ml), avanafil (2.81 µg/ml), viroptic (4.286 µg/ml), pitavastatin (10.02 µg/ml), and pioglitazone (55.3 µg/ml).The identification of dapagliflozin, pioglitazone, pitavastatin, and avanafil as potent AR inhibitors is significant, as these are already approved for other therapeutic uses. This suggests that repurposing certain FDA-approved drugs could provide effective AR inhibitors with potential for treating diabetic complications. Further in vivo studies are recommended to validate these findings.