SAR and 3D-QSAR Studies on Thiadiazolidinone Derivatives: Exploration of Structural Requirements for Glycogen Synthase Kinase 3 Inhibitors
| Autor: | Concepción Pérez, Ana Martínez, F. Javier Luque, Francisco J. Moreno, J. Luis Gelpi, Isabel Dorronsoro, Ana I. Gómez de Castro, Mercedes Alonso |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Models
Molecular Quantitative structure–activity relationship Binding Sites Rhodanine biology Molecular model Chemistry Stereochemistry Hydantoins Heteroatom Quantitative Structure-Activity Relationship Chemical synthesis Maleimides Turn (biochemistry) Glycogen Synthase Kinase 3 Structure-Activity Relationship GSK-3 Enzyme inhibitor Thiadiazoles Drug Discovery biology.protein Molecular Medicine Protein kinase A Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry. 48:7103-7112 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm040895g |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|