Pursuing aldose reductase inhibitors through in situ cross-docking and similarity-based virtual screening

Aldose reductase (ALR2) is a critical enzyme in the development of the major complications of diabetes mellitus. Herein, new molecular entities active against ALR2 were discovered through an integrated receptor- and ligand-based virtual screening campaign. Twelve candidates were found to inhibit this enzyme in the micromolar range including two ligands having an IC50 below 3 μM. Six new compounds, structurally unrelated to the known ARIs, have been identified, opening up opportunity for lead optimization. © 2009 American Chemical Society.