Glycogen Synthase Kinase 3 (GSK3) Targeted Library

Glycogen Synthase Kinase 3 (GSK3) is a serine/threonine protein kinase with two isoforms: GSK3α and GSK3β [1]. The main differences between GSK3α and GSK3β are that GSK3β is expressed in cells of various tissues, whereas GSK3α is expressed mainly in brain cells, testis, and skeletal muscle [2]. The regulation is also slightly different. GSK3β is regulated by phosphorylation on residues Ser9 and Tyr216, while GSK3α is regulated by phosphorylation on residues Tyr279 and Tyr216 [3]. Both enzymes act as negative regulators of hormonal control of glucose homeostasis, Wnt signaling, and regulation of transcription factors and microtubules by phosphorylating and inactivating glycogen synthase [4]. GSK3 has many substrates: signaling proteins, structural proteins, and neural cell adhesion proteins [5].

Given this large number of substrates, GSK3 can, directly and indirectly, affect many metabolic pathways and be involved in the development of many diseases. For example, GSK3 can alter the activity of NF-κB, which is often expressed at high levels in cancer cells [6]. GSK3β is implicated in Alzheimer's disease because it is involved in tau phosphorylation [7]. GSK3 is also involved in retinal degeneration [8]. Given these critical facts, searching for new selective inhibitors of this kinase is among leading challenges for the pharmaceutical industry to create new drugs.

Since GSK-3 plays a crucial role in the pathogenesis of the above-mentioned serious diseases, the Life Chemicals team has developed a dedicated Docking Library of over 2,700 unique drug-like screening compounds to contribute to the development of new effective medicines.

The compound selection can be customized based on your requirements, cherry picking is available.

Please, contact us at orders@lifechemicals.com for any additional information and price quotations.

Figure 1. Examples of compounds with the best values of docking scores from the GSK3 Targeted Library.

Compound selection

High-throughput virtual screening and molecular fitting were performed on the protein structure of 1Q4L PDB [9]. The compounds used for docking were selected from the Life Chemicals HTS Compound Collection. The compound selection was refined by PAINS, toxic and reactive filters, followed by the in-house MedChem filters to obtain over 2,700 drug-like screening compounds.

Key features:

• Method: high-throughput virtual screening (docking), molecular fitting
• X-Ray data used: 1Q4L
• Constraints: no
• Filters used: PAINS, toxic, reactive
• Number of compounds selected: 2758

Figure 2 Spatial structure binding site of the complex of GSK-3 Beta with lead docking molecule F2565-0331.

References

1. Patel P, Woodgett JR. Glycogen Synthase Kinase 3: A Kinase for All Pathways?. Curr Top Dev Biol. 2017;123:277-302. doi:10.1016/bs.ctdb.2016.11.011
2. Ma YX, Wang XL, Chen JQ, Li B, Hur EM, Saijilafu. Differential Roles of Glycogen Synthase Kinase 3 Subtypes Alpha and Beta in Cortical Development. Front Mol Neurosci. 2017;10:391. Published 2017 Nov 28. doi:10.3389/fnmol.2017.00391
3. Beurel E, Grieco SF, Jope RS. Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases. Pharmacol Ther. 2015;148:114-131. doi:10.1016/j.pharmthera.2014.11.016
4. Kaidanovich-Beilin O, Woodgett JR. GSK-3: Functional Insights from Cell Biology and Animal Models. Front Mol Neurosci. 2011;4:40. Published 2011 Nov 16. doi:10.3389/fnmol.2011.00040
5. Wadhwa P, Jain P, Jadhav HR. Glycogen Synthase Kinase 3 (GSK3): Its Role and Inhibitors. Curr Top Med Chem. 2020;20(17):1522-1534. doi:10.2174/1568026620666200516153136
6. Duda P, Akula SM, Abrams SL, et al. Targeting GSK3 and Associated Signaling Pathways Involved in Cancer. Cells. 2020;9(5):1110. Published 2020 Apr 30. doi:10.3390/cells9051110
7. Gizak A, Duda P, Pielka E, McCubrey JA, Rakus D. GSK3 and miRNA in neural tissue: From brain development to neurodegenerative diseases. Biochim Biophys Acta Mol Cell Res. 2020;1867(7):118696. doi:10.1016/j.bbamcr.2020.118696
8. Hottin C, Perron M, Roger JE. GSK3 Is a Central Player in Retinal Degenerative Diseases but a Challenging Therapeutic Target. Cells. 2022;11(18):2898. Published 2022 Sep 16. doi:10.3390/cells11182898
9. Bertrand JA, Thieffine S, Vulpetti A, et al. Structural characterization of the GSK-3beta active site using selective and non-selective ATP-mimetic inhibitors. J Mol Biol. 2003;333(2):393-407. doi:10.1016/j.jmb.2003.08.031