In silico exploration for aldose reductase (AR) inhibitors

Abstract

Aldose reductase plays a role in glucose metabolism in the polyol pathway responsible for complications of diabetes mellitus. In this study, pharmacophore modeling and molecular docking were conducted to identify hit compounds as inhibitors of aldose reductase (AR). The pharmacophore feature consists of two hydrogen-bond acceptors, four hydrophobics and one aromatic ring feature with Area Under Curve of Receiver Operating Characteristics (AUC-ROC) is 0.53 and the Goodness of Hit (GH) value is 0.76. Screening in the ZINC database generated 1,225 hit compounds, were subjected to molecular docking to determine their binding energy and interactions with AR. The range of binding energy (E) of all hit compounds is -8.81 to -14.22 kcal/mol and there are four best hit compounds namely Lig_234, Lig_873, Lig_1, and Lig_902, when compared to native ligands (3NA, E= -12.98 kcal/mol) based on their binding energy and orientation, which indicate their potential as new AR inhibitors.