Identification of small molecules that inhibit GSK-3β through virtual screening

Nam Sook Kang, Gil Nam Lee, Chi Hyun Kim, Myung Ae Bae, Ikyon Kim, Young Sik Cho

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12 Citations (Scopus)


Glycogen synthase kinase-3β (GSK-3β) is involved in glycogen metabolism, neuronal cell development, osteoblast differentiation. Small molecule inhibitors of GSK-3β have various therapeutic potential for the treatment of diabetes type II, bipolar disorders, stroke and chronic inflammatory disease. To identify GSK-3β inhibitors with novel scaffold from chemical library, we primarily screened out putative inhibitors through computer modeling and subsequently evaluated the inhibitory activity of selected compounds against GSK-3β by in vitro Z'-LYTE™ assay. A series of compound KRMs strongly inhibited phosphorylation of its substrate with IC50 value of approximately 0.5 μM. Also, we demonstrated that KRM-189 and KRM-191 competed with ATP for GSK-3β, leading to decreased Vmax and constant Km with increasing concentrations of ATP as determined from Lineweaver-Berk equation. Moreover, they showed the selectivity for GSK-3β over other kinases with IC50 values of 2 to 10 μM or more Incubation of cells with KRM-191 with highly selective and potent inhibitory activity caused accumulation of β-catenin, downstream of GSK-3β signaling pathway, indicating that small molecule can prevent degradation of β-catenin via GSK-3β inhibition. Our results suggest that modeling in combination with in vitro assays can be used for the identification of selective and potent inhibitors.

Original languageEnglish
Pages (from-to)533-537
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Issue number2
Publication statusPublished - 2009 Jan 15

Bibliographical note

Funding Information:
This research was supported by the Center for Biological, Modulators of the 21st Century Frontier R&D Program, Ministry of Science and Technology, Korea.

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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