Beyond boundaries: pioneering discoveries in aldose reductase inhibition for diabetic neuropathy

Aldose reductase enzyme is involved in key step controlling the polyolpathway and acknowledged as a possible target for diabetic neuropathy. Theanionic region of the active site comprising residues His110 and Tyr48 isinvolved in the detoxification mechanism that is considered important. Thisprocess involves eliminating toxicity through conversion of aldehydes suchas methylglyoxal (MeG) and 3-deoxyglucosone. So far, no drug has beendeveloped that could selectively inhibit reduction of glucose to sorbitol withoutaffecting the detoxification mechanism. To comprehend the critical interactionsof the known aldose reductase inhibitors and the enzyme, molecular dockingwas conducted in this study. Anionic region, specificity region and the activesite are the three regions used separately for grid molecular docking studiesto identify the possible inhibitors that selectively bind to specificity region.Among the docked compounds, quercetin was found to bind to specificityregion, so we chose reported quercetin analogue and built a pharmacophoremodel. Subsequently, a collection of 82,000 natural substances from the IBSdatabank (InterBioScreen) was searched using a 6-point pharmacophore(AAARRR) that was created. After the initial search returned 2,394 hits, ahierarchical docking approach was used to identify an intriguing hit molecule(mol_7921), which is quite close to a flavonoid compound. Moleculardynamics simulation was used to confirm the hit molecule-aldose reductasecomplex’s structural stability. For its possible inhibitory effect, this moleculecould be tested and used to treat diabetic neuropathy