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Identification of CNS compatible small molecules as glycogen synthase kinase-3β (GSK-3β) inhibitors through structure-based virtual screening

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cris.lastimport.scopus2024-02-12T19:35:46Z
dc.abstract.enAlzheimer’s Disease (AD) is one of the significant diseases of the aging population and affects Central Nervous System dominantly. Blood-brain-barrier permeation is a substantial complication in developing CNS drugs, and it is considered challenging with minimal success rates. Although Glycogen synthase kinase-3β (GSK-3β) is an attractive disease-modifying target for AD, there is no single GSK-3β inhibitor in clinical trials for AD. Here we performed structure-based virtual screening on the Chembridge CNS-Set library compounds. 10 hits were identified based on interaction, binding energy, dock score, and a potential ADME profile. These 10 chosen compounds were then investigated for in vitro kinase inhibitory activity against GSK-3β and other AD-related kinases. Among these, the molecule 7114202 showed 48% GSK-3β inhibition while showing selectivity over other AD-related kinases. Molecular dynamic simulations of apoenzyme, co-crystallized molecule, and 7114202 validated the Lys85, Val135, Leu188, Asp200 located in the active site of enzyme play a significant role in GSK-3β complex formation with inhibitors, and they are responsible for activity and selectivity. The in vitro studies also revealed a potent and selective Casein Kinase 1ε (CK1ε) inhibitor 7774767 with IC50 5.10 µM.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorMalik, Ruch
dc.contributor.authorFilipek, Sławomir
dc.contributor.authorJain, Pakhuri
dc.contributor.authorChoudhary, Bhanwar Singh
dc.contributor.authorSukanya, Sukanya
dc.date.accessioned2024-01-25T03:35:06Z
dc.date.available2024-01-25T03:35:06Z
dc.date.issued2022
dc.description.financeNie dotyczy
dc.description.number9
dc.description.volume31
dc.identifier.doi10.1007/S00044-022-02912-Z
dc.identifier.issn1054-2523
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/108864
dc.identifier.weblinkhttps://link.springer.com/content/pdf/10.1007/s00044-022-02912-z.pdf
dc.languageeng
dc.pbn.affiliationchemical sciences
dc.relation.ispartofMedicinal Chemistry Research
dc.relation.pages1545-1557
dc.rightsClosedAccess
dc.sciencecloudnosend
dc.subject.enAlzheimer’sdisease ● Structure-based virtual screening ● Glycogen synthase kinase-3β ● Kinase inhibitory assay ● Molecular dynamic simulation
dc.titleIdentification of CNS compatible small molecules as glycogen synthase kinase-3β (GSK-3β) inhibitors through structure-based virtual screening
dc.typeJournalArticle
dspace.entity.typePublication