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- Title
Pharmacophore Modeling, Ensemble Docking, Virtual Screening, and Biological Evaluation on Glycogen Synthase Kinase-3β.
- Authors
Fu, Gang; Sivaprakasam, Prasanna; Dale, Olivia R.; Manly, Susan P.; Cutler, Stephen J.; Doerksen, Robert J.
- Abstract
Glycogen synthase kinase-3 (GSK-3) is a multifunctional serine/threonine protein kinase which is engaged in a variety of signaling pathways, regulating a wide range of cellular processes. GSK-3β, also known as tau protein kinase I (TPK-I), is one of the most important kinases implicated in the hyperphosphorylation of tau that leads to neurodegenerative diseases. Hence, GSK-3β has emerged as an important therapeutic target. To identify compounds that are structurally novel and diverse compared to previously reported ATP-competitive GSK-3β inhibitors, we performed virtual screening by implementing a mixed ligand/structure-based approach, which included pharmacophore modeling, diversity analysis, and ensemble docking. The sensitivities of different docking protocols to induced-fit effects were explored. An enrichment study was employed to verify the robustness of ensemble docking, using 13 X-ray structures of GSK-3β, compared to individual docking in terms of retrieving active compounds from a decoy dataset. A total of 24 structurally diverse compounds obtained from the virtual screening underwent biological validation. The bioassay results showed that 15 out of the 24 hit compounds are indeed GSK-3β inhibitors, and among them, one compound exhibiting sub-micromolar inhibitory activity is a reasonable starting point for further optimization.
- Subjects
GLYCOGEN synthase kinase-3; SERINE/THREONINE kinases; TAU proteins; RISK factors of neurodegeneration; LIGANDS (Biochemistry); MOLECULAR structure of ligands
- Publication
Molecular Informatics, 2014, Vol 33, Issue 9, p610
- ISSN
1868-1743
- Publication type
Article
- DOI
10.1002/minf.201400044