Insights into the interactions between maleimide derivates and GSK3β combining molecular docking and QSAR
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Archivos
Fecha
2014-07
Profesor/a Guía
Facultad/escuela
Idioma
en
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Título del volumen
Editor
Public Library of Science
Nombre de Curso
Licencia CC
Atribution 4.0 International (CC BY 4.0)
Licencia CC
https://creativecommons.org/licenses/by/4.0/deed.es
Resumen
Many protein kinase (PK) inhibitors have been reported in recent years, but only a few have been approved for clinical use.
The understanding of the available molecular information using computational tools is an alternative to contribute to this
process. With this in mind, we studied the binding modes of 77 maleimide derivates inside the PK glycogen synthase kinase
3 beta (GSK3b) using docking experiments. We found that the orientations that these compounds adopt inside GSK3b
binding site prioritize the formation of hydrogen bond (HB) interactions between the maleimide group and the residues at
the hinge region (residues Val135 and Asp133), and adopt propeller-like conformations (where the maleimide is the
propeller axis and the heterocyclic substituents are two slanted blades). In addition, quantitative structure–activity
relationship (QSAR) models using CoMSIA methodology were constructed to explain the trend of the GSK3b inhibitory
activities for the studied compounds. We found a model to explain the structure–activity relationship of non-cyclic
maleimide (NCM) derivatives (54 compounds). The best CoMSIA model (training set included 44 compounds) included
steric, hydrophobic, and HB donor fields and had a good Q2 value of 0.539. It also predicted adequately the most active
compounds contained in the test set. Furthermore, the analysis of the plots of the steric CoMSIA field describes the
elements involved in the differential potency of the inhibitors that can be considered for the selection of suitable inhibitors.
Notas
Indexación: Scopus.
Palabras clave
Protein Kinases, Crystal Structure, Heterocyclic Compounds, Lysine, Dihedral Angles, Heterocyclic Compounds, Ovarian Cancer, Pancreatic Cancer, Phosphorylation
Citación
PLoS ONE. Volume 9, Issue 7. 10 July 2014. Article number e102212
DOI
DOI: 10.1371/journal.pone.0102212