title: Molecular dynamics study of the inhibitory effects of ChEMBL474807 on the enzymes GSK-3β and CDK-2.
abstract: Indirubin derivatives and analogs comprise a significant group of ATP-competitive inhibitors. The inhibitory effects of ChEMBL474807 (1-(4-amino-1,2,5-oxadiazol-3-yl)-5-(piperidin-1-ylmethyl)-N'-(pyridin-4-ylmethylene)-1H-1,2,3-triazole-4-carbohydrazide) on two enzymes, namely glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent kinase-2 (CDK-2), were analyzed. The close resemblance of the amino acid sequences of these two enzymes (with 25% identity and 41% similarity) explains why indirubin derivatives are inhibitors of both of the enzymes studied. The docking and molecular dynamics investigation performed here led to the identification of the interactions responsible for stabilizing the ligand ChEMBL474807 at the active sites of the enzymes considered. The structural and energetic data collected during our investigations clearly indicate that there are important differences in the behavior of the ligand at the two active sites investigated here.
authors.affiliation: Department of Physical Chemistry, Collegium Medicum, Nicolaus Copernicus University, Kurpinskiego 5, 85-950, Bydgoszcz, Poland, przemekcz@cm.umk.pl.
authors.forename: Przemysław
authors.initials: P
authors.lastname: Czeleń
authors.forename: Beata
authors.initials: B
authors.lastname: Szefler
mesh_terms: D020134:Catalytic Domain; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology
chemical_list: D007211:Indoles; D008024:Ligands; D047428:Protein Kinase Inhibitors; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D038362:Glycogen Synthase Kinase 3; C027185:indirubin