Computational screening identifies selective aldose reductase inhibitors with strong efficacy and limited off target...

Diabetes mellitus is characterized by persistent hyperglycemia that triggers micro-vascular complications in organs such as the eyes and kidneys; a pivotal enzymatic driver is aldose reductase (AR), which reduces glucose to sorbitol. Because existing AR inhibitors often cause off-target toxicity, we implemented an integrative in-silico workflow to discover selective, safer compounds. A library of 4 975 small molecules was docked against AR and, in parallel, against five clinically relevant antitarget proteins or proteins whose unintended inhibition is associated with adverse pharmacological or toxicological effects (CYP2A6, CYP2C9, CYP3A4, SULT1A3 and the pregnane X receptor), retaining 236 ligands whose binding energies to every antitarget were weaker than those of the reference drug tolrestat. These survivors were redocked to five high-resolution human AR crystal structures, and the ten best-scoring ligands underwent 100 ns molecular-dynamics simulations followed by MM-PBSA free-energy calculations to refine affinity estimates and probe complex stability. Ligand 4934, a benzo[a]anthracene-pyrene polyphenol, displayed the strongest predicted affinity for while showing poor affinity for the antitarget panel, outperforming tolrestat by more than 2 kcal mol⁻¹ and adopting a stable plug-like pose that occludes the catalytic pocket through extensive π-π and hydrophobic contacts with Trp111, Phe123 and Lys22. These findings highlight ligand 4934 as a promising scaffold for selective AR inhibition and demonstrate the effectiveness of the stepwise computational strategy in prioritizing lead compounds with reduced off-target liabilities.