title: Naproxen and cromolyn as new glycogen synthase kinase 3β inhibitors for amelioration of diabetes and obesity: an investigation by docking simulation and subsequent in vitro/in vivo biochemical evaluation.
abstract: Naproxen and cromolyn were investigated as new inhibitors of glycogen synthase kinase-3β (GSK-3β) in an attempt to explain their hypoglycemic properties. Study included simulated docking experiments, in vitro enzyme inhibition assay, and in vivo validations. Both drugs not only were optimally fitted within a GSK-3β binding pocket via several attractive interactions with key amino acids but also exhibited potent in vitro enzymatic inhibitory activities of IC50 1.5 and 2.0 µM for naproxen and cromolyn, respectively. In vivo experiments illustrated that both drugs significantly reduced serum glucose and increased hepatic glycogen- and serum insulin levels in normal and type II diabetic Balb/c mice models. In obese animal model, both drugs exhibited significant reduction in mice weights, serum glucose, and resistin levels along with significant elevation in serum insulin, C-peptide, and adiponectin values. It can be concluded that naproxen and cromolyn are novel GSK-3β inhibitors and can help in management of diabetes and obesity.
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
authors.forename: Tarek M K
authors.initials: TM
authors.lastname: Motawi
authors.forename: Yasser
authors.initials: Y
authors.lastname: Bustanji
authors.forename: Shohda A
authors.initials: SA
authors.lastname: El-Maraghy
authors.forename: Mutasem O
authors.initials: MO
authors.lastname: Taha
authors.forename: Mohamed A S
authors.initials: MA
authors.lastname: Al Ghussein
mesh_terms: D000818:Animals; D001665:Binding Sites; D004205:Cromolyn Sodium / Q000008:administration & dosage*; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000201:enzymology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D009288:Naproxen / Q000008:administration & dosage*; D009765:Obesity / Q000188:drug therapy* / Q000201:enzymology; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D009288:Naproxen; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D004205:Cromolyn Sodium
keywords: Cromolyn; Docking Simulation; Glycogen; Glycogen Synthase Kinase-3β; Naproxen; Resistin