title: Validation of TZD Scaffold as Potential ARIs: Pharmacophore Modeling, Atom-based 3D QSAR and Docking Studies.
abstract: 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 inhibitory activity.
  
  
  RESULTS
  The result of these studies may account to design a legitimate template for rational drug design of novel, potent and promising ALR2 inhibitors.
authors.affiliation: University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160014. India.
authors.forename: Lalita
authors.initials: L
authors.lastname: Dahiya
authors.affiliation: University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160014. India.
authors.forename: Manoj Kumar
authors.initials: MK
authors.lastname: Mahapatra
authors.affiliation: University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160014. India.
authors.forename: Ramandeep
authors.initials: R
authors.lastname: Kaur
authors.affiliation: Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Bandar Sindri, Ajmer, Rajasthan- 305817. India.
authors.forename: Vipin
authors.initials: V
authors.lastname: Kumar
authors.affiliation: University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160014. India.
authors.forename: Manoj
authors.initials: M
authors.lastname: Kumar
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D021281:Quantitative Structure-Activity Relationship; D045162:Thiazolidinediones / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D045162:Thiazolidinediones; C500090:thiazolidine-2,4-dione; C484670:AKR1B1 protein, human; D000449:Aldehyde Reductase
keywords: 3D-QSAR; ALR2; diabetes; docking; pharmacophore hypothesis; phase