Objective: Metabolic disorders associated with diabetic patients are a serious concern.
Aldose reductase (ALR2) has been identified as first rate-limiting enzyme in the polyol pathway
which catalyzes the reduction of glucose to sorbitol. It represents one of the validated targets to
develop potential new chemical entities for the prevention and subsequent progression of
microvascular diabetic complications. In order to further understand the intricate structural
prerequisites of molecules to act as ALR2 inhibitors, ligand-based pharmacophore model, atombased
3D-QSAR and structure based drug design studies have been performed on a series of 2,4-
thiazolidinedione derivatives with ALR2 inhibitory activity.
Methods: In the present study, a validated six point pharmacophore model (AAADNR) with three
hydrogen bond acceptor (A), one hydrogen bond donor (D), one negative ionic group (N) and one
aromatic ring (R) was developed using PHASE module of Schrodinger suite with acceptable PLS
statistics (survival score = 3.871, cross-validated correlation coefficient Q2
= 0.6902, correlation
coefficient of multiple determination r2
= 0.9019, Pearson-R coefficient = 0.8354 and F distribution
= 196.2). In silico
predictive studies (pharmacophore modeling, atom-based 3D QSAR and docking
combined with drug receptor binding free energetics and pharmacokinetic drug profile) highlighted
some of the important structural features of thiazolidinedione analogs required for potential ALR2
Results: The result of these studies may account to design a legitimate template for rational drug
design of novel, potent and promising ALR2 inhibitors.