In silico approaches to develop new phenyl-pyrimidines as glycogen synthase kinase 3 (GSK-3) inhibitors with halogen-bonding capabilities : 3D-QSAR CoMFA/CoMSIA, molecular docking and molecular dynamics studies
dc.creator | Universidad San Sebastián | |
dc.creator | Universidad San Sebastián | |
dc.creator | Universidad San Sebastián | |
dc.creator | Universidad San Sebastián | |
dc.creator | Universidad San Sebastián | |
dc.creator | Universidad San Sebastián | |
dc.creator | Cabezas, David | |
dc.creator | Mellado, Guido | |
dc.creator | Espinoza, Nicolás | |
dc.creator | Gárate, José Antonio | |
dc.creator | Morales, César | |
dc.creator | Castro-Alvarez, Alejandro | |
dc.creator | Matos, Maria J. | |
dc.creator | Mellado, Marco | |
dc.creator | Mella, Jaime | |
dc.date.accessioned | 2023-05-24T04:50:48Z | |
dc.date.available | 2023-05-24T04:50:48Z | |
dc.date.created | 2023-05-24T04:50:48Z | |
dc.date.issued | 2023 | |
dc.identifier | 0739-1102 | |
dc.identifier | https://repositorio.uss.cl/handle/uss/6332 | |
dc.identifier | 10.1080/07391102.2023.2172457 | |
dc.description.abstract | Glycogen synthase kinase 3 (GSK-3) is involved in different diseases, such as manic-depressive illness, Alzheimer’s disease and cancer. Studies have shown that insulin inhibits GSK-3 to keep glycogen synthase active. Inhibiting GSK-3 may have an indirect pro-insulin effect by favouring glycogen synthesis. Therefore, the development of GSK-3 inhibitors can be a useful alternative for the treatment of type II diabetes. Aminopyrimidine derivatives already proved to be interesting GSK-3 inhibitors. In the current study, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) have been performed on a series of 122 aminopyrimidine derivatives in order to generate a robust model for the rational design of new compounds with promising antidiabetic activity. The q 2 values obtained for the best CoMFA and CoMSIA models have been 0.563 and 0.598, respectively. In addition, the r 2 values have been 0.823 and 0.925 for CoMFA and CoMSIA, respectively. The models were statistically validated, and from the contour maps analysis, a proposal of 10 new compounds has been generated, with predicted pIC50 higher than 9. The final contribution of our work is that: (a) we provide an extensive structure–activity relationship for GSK-3 inhibitory pyrimidines; and (b) these models may speed up the discovery of GSK-3 inhibitors based on the aminopyrimidine scaffold. Finally, we carried out docking and molecular dynamics studies of the two best candidates, which were shown to establish halogen-bond interactions with the enzyme. Communicated by Ramaswamy H. Sarma. | |
dc.language | eng | |
dc.relation | Journal of Biomolecular Structure and Dynamics | |
dc.title | In silico approaches to develop new phenyl-pyrimidines as glycogen synthase kinase 3 (GSK-3) inhibitors with halogen-bonding capabilities : 3D-QSAR CoMFA/CoMSIA, molecular docking and molecular dynamics studies | |
dc.type | Artículo |