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

Nagarajan A., Vignesh C., Ramasamy T., Sasikala M., Mohan S.

Abstract


Aldose reductase enzyme is involved in key step controlling the polyol pathway and acknowledged as a possible target for diabetic neuropathy. The anionic region of the active site comprising residues His110 and Tyr48 is involved in the detoxification mechanism that is considered important. This process involves eliminating toxicity through conversion of aldehydes such as methylglyoxal (MeG) and 3-deoxyglucosone. So far, no drug has been developed that could selectively inhibit reduction of glucose to sorbitol without affecting the detoxification mechanism. To comprehend the critical interactions of the known aldose reductase inhibitors and the enzyme, molecular docking was conducted in this study. Anionic region, specificity region and the active site are the three regions used separately for grid molecular docking studies to identify the possible inhibitors that selectively bind to specificity region. Among the docked compounds, quercetin was found to bind to specificity region, so we chose reported quercetin analogue and built a pharmacophore model. Subsequently, a collection of 82,000 natural substances from the IBS databank (InterBioScreen) was searched using a 6-point pharmacophore (AAARRR) that was created. After the initial search returned 2,394 hits, a hierarchical docking approach was used to identify an intriguing hit molecule (mol_7921), which is quite close to a flavonoid compound. Molecular dynamics simulation was used to confirm the hit molecule-aldose reductase complex’s structural stability. For its possible inhibitory effect, this molecule could be tested and used to treat diabetic neuropathy.


Keywords


diabetic neuropathy, polyol pathway, methylglyoxal, quercetin, virtual screening, inhibitors

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