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

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 q² values obtained for the best CoMFA and CoMSIA models have been 0.563 and 0.598, respectively. In addition, the r² 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

Keywords:

• Type II diabetes
• insulin
• glycogen synthase kinase 3
• pyrimidine
• 3D-QSAR

Acknowledgments

The authors thank the Agencia Nacional de Investigación y Desarrollo (ANID), Dirección de Investigación y Postgrado from the Universidad Central de Chile, as well as to Instituto de Investigación y Postgrado from the Universidad Central de Chile.

Author’s Contributions

Conceptualization, M.J.M. M.M. and J.M.; methodology, D.C., G.M. and N.E.; software, J.A.G., C.M., and A.C.A.; validation, D.C.; formal analysis, D.C. and J.M.; resources, M.J.M., C.M., and A.C.A.; data curation, D.C. and G.M.; writing—original draft preparation, M.M., M.J.M. and J.M.; writing—M.J.M., J.M.; supervision, M.M., M.J.M, and J.M.; project administration, J.M.; funding acquisition, M.M. and M.J.M. All authors have read and agreed to the published version of the manuscript.

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

This research was funded by Agencia Nacional de Investigación y Desarrollo (ANID) through the following programs Fondecyt grant No 1221260 to J.AG. and Convocatoria Nacional Subvención a Instalación en la Academia año 2021 Folio SA77210078 to M.M. The Nucleus in Nano Biophysics is funded by the Millennium Science Initiative Program ICM-ANID through grant NCN2021_021 (N.E., J.A.G). Centro Ciencia y Vida, Financiamiento Basal para Centros Científicos y Tecnológicos de Excelencia de ANID FB210008, (J.A.G).