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.
Highlights
Glycogen synthase kinase-3 (GSK-3) is a multitasking serine/threonine protein kinase
A GSK-3 receptor (PDB ID: 1PYX) and ligands were prepared for virtual screening by adding the hydrogen atoms and by removing all water molecules that were co-crystallized with this target protein
Pharmacophore search The structure of the Tideglusib compound was initially downloaded from the ZINC database (ZINC13985228) in the .mol2 format and its energy was minimized using the CHARMM force field implemented in the Accelrys discovery studio
Summary
Glycogen synthase kinase-3 (GSK-3) is a multitasking serine/threonine protein kinase. GSK-3 is a twodomain kinase fold, with a β-strand domain and an α-helix domain. The β-strand domain (residues 25–138) is located at the N-terminal end and comprises seven antiparallel β-strands interrupted by a short helix (residues 96–102) comprising highly conserved residues. The Arg residue is involved in domain alignment, whereas the Glu residue that forms a salt bridge with Lys plays a crucial role in the catalytic activity of the enzyme. The α-helical domain comprises residues 139–343 forms at the C-terminal end. The catalytic site is located at the interface of the α-helical and β-strand domains and is surrounded by a hinge region and a glycine-rich loop. The activation loop is formed with residues 200-226 near the substrate binding site [1]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
