Olanzapine inhibits glycogen synthase kinase-3beta: an investigation by docking simulation and experimental validation.
Olanzapine was investigated as an inhibitor of glycogen synthase kinase-3beta (GSK-3beta) in an attempt to evaluate its effect on blood glucose level. The investigation included simulated docking experiments to fit olanzapine within the binding pocket of GSK-3beta followed by in vitro enzyme inhibition assay as well as in vivo subchronic animal treatment. Olanzapine was found to readily fit within the binding pocket of GSK-3beta in a low energy orientation characterized with optimal attractive interactions bridging the tricyclic thienobenzodiazepine nitrogen and sulfur atoms of olanzapine and the residue of VAL-135 of GSK-3beta. In vivo experiments showed a significant decrease in fasting blood glucose level in Balb/c mice at 1.0, 2.0 and 3.0 mg/kg dose levels (P<0.05) and 6 fold increase in liver glycogen level at the 3 mg/kg dose level (P<0.001). Moreover; olanzapine was found to potently inhibit recombinant GSK-3beta in vitro (IC(50) value=91.0 nM). Our findings strongly suggest that olanzapine has significant GSK-3beta inhibition activity that could justify some of its pharmacological effects and glucose metabolic disturbances.
Mohammad
Mohammad K
MK
Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Jordan, Amman 11942, Jordan. mkmohammad@ju.edu.jo
Al-Masri
Ihab M
IM
Taha
Mutasem O
MO
Al-Ghussein
Mohamed A S
MA
Alkhatib
Hatim S
HS
Najjar
Samer
S
Bustanji
Yasser
Y
D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001569:Benzodiazepines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D001786:Blood Glucose / Q000187:drug effects; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006003:Glycogen / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015394:Molecular Structure; D000077152:Olanzapine; D010865:Pilot Projects; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D015203:Reproducibility of Results
D014150:Antipsychotic Agents; D001786:Blood Glucose; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D001569:Benzodiazepines; D006003:Glycogen; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D000077152:Olanzapine