3D-QSAR and docking studies of selective GSK-3beta inhibitors. Comparison with a thieno[2,3-b]pyrrolizinone derivative, a new potential lead for GSK-3beta ligands.
The three-dimensional structures of 3-anilino-4-arylmaleimides, selective GSK-3beta inhibitors, were correlated to their biological affinities by 3D-QSAR studies (CoMFA method). The cocrystallographic data of GSK-3beta vs 3-anilino-4-arylmaleimide allowed us to compare 3D-QSAR results to experimental intermolecular interactions. The results of the CoMFA analysis did not really correspond to the interactions recorded in the active site, but they characterized fundamental features (areas of the active site) of the interactions ligand-receptor. These studies were the starting point to analyze a new GSK-3beta ligand, a thieno[2,3-b]pyrrolizinone derivative. This comparison based on docking and simulation approaches allowed us to confirm one preferential orientation of this ligand inside the active site, explaining the relationship with the reference 3-anilino-4-arylmaleimide derivatives and its biological affinity.
Lescot
Elodie
E
Centre d'Etudes et de Recherche sur le Médicament de Normandie, Université de Basse-Normandie, 5, rue Vaubénard, 14032 Caen, France.
Bureau
Ronan
R
Sopkova-de Oliveira Santos
Jana
J
Rochais
Christophe
C
Lisowski
Vincent
V
Lancelot
Jean-Charles
JC
Rault
Sylvain
S
D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008024:Ligands; D008958:Models, Molecular; D011758:Pyrroles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
D004791:Enzyme Inhibitors; D008024:Ligands; D011758:Pyrroles; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3