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Pharmacophore feature-based virtual screening for finding potent GSK-3 inhibitors using molecular docking and dynamics simulations
- Source :
- Bioinformation
- Publication Year :
- 2016
-
Abstract
- Glycogen synthase kinase-3 (GSK-3) is a multitasking serine/threonine protein kinase, which is associated with the pathophysiology of several diseases such as diabetes, cancer, psychiatric and neurodegenerative diseases. Tideglusib is a potent, selective, and irreversible GSK-3 inhibitor that has been investigated in phase II clinical trials for the treatment of progressive supranuclear palsy and Alzheimer's disease. In the present study, we performed pharmacophore feature-based virtual screening for identifying potent targetspecific GSK-3 inhibitors. We found 64 compounds that show better GSK-3 binding potentials compared with those of Tideglusib. We further validated the obtained binding potentials by performing 20-ns molecular dynamics simulations for GSK-3 complexed with Tideglusib and with the best compound found via virtual screening in this study. Several interesting molecular-level interactions were identified, including a covalent interaction with Cys199 residue at the entrance of the GSK-3 active site. These findings are expected to play a crucial role in the binding of target-specific GSK-3 inhibitors.
- Subjects :
- 0301 basic medicine
Virtual screening
GSK-3
biology
Chemistry
Tideglusib
General Medicine
Computational biology
macromolecular substances
Hypothesis
Molecular dynamics
Docking
Serine
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
Protein–ligand docking
Docking (molecular)
biology.protein
Pharmacophore
Glycogen synthase
Protein kinase A
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 09732063
- Volume :
- 12
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Bioinformation
- Accession number :
- edsair.doi.dedup.....6fc4ba1474347ac87aa79feac865888c