title: SAR and 3D-QSAR studies on thiadiazolidinone derivatives: exploration of structural requirements for glycogen synthase kinase 3 inhibitors.
abstract: The 2,4-disubstituted thiadiazolidinones (TDZD) are described as the first ATP-noncompetitive GSK-3 inhibitors. Following an SAR study about TDZD, different structural modifications in the heterocyclic ring aimed to test the influence of each heteroatom on the biological study are here reported here. Various compounds such as hydantoins, dithiazolidindiones, rhodanines, maleimides, and triazoles were synthesized and screened as GSK-3 inhibitors. After an extensive SAR study among these different heterocyclic families, TDZDs have been revealed as a privileged scaffold for the selective inhibition of GSK-3. A CoMFA analysis was also performed highlighting the molecular electrostatic field interaction in the interaction of TDZDs with GSK-3. Moreover, first mapping studies indicate two binding modes which in turn might imply relevant differences in the mechanism that underly the inhibitory activity of TDZDs.
authors.affiliation: Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain. amartinez@neuropharma.es
authors.forename: Ana
authors.initials: A
authors.lastname: Martinez
authors.forename: Mercedes
authors.initials: M
authors.lastname: Alonso
authors.forename: Ana
authors.initials: A
authors.lastname: Castro
authors.forename: Isabel
authors.initials: I
authors.lastname: Dorronsoro
authors.forename: J Luis
authors.initials: JL
authors.lastname: Gelpí
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Luque
authors.forename: Concepción
authors.initials: C
authors.lastname: Pérez
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Moreno
mesh_terms: D001665:Binding Sites; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006827:Hydantoins / Q000138:chemical synthesis / Q000737:chemistry; D008301:Maleimides / Q000138:chemical synthesis / Q000737:chemistry; D008958:Models, Molecular; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D012236:Rhodanine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D006827:Hydantoins; D008301:Maleimides; D013830:Thiadiazoles; D012236:Rhodanine; D038362:Glycogen Synthase Kinase 3