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Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Design of Glycogen Synthase Kinase-3 Inhibitors: An Overview on Recent Advancements

Author(s): Minhajul Arfeen and Prasad V. Bharatam

Volume 19, Issue 26, 2013

Page: [4755 - 4775] Pages: 21

DOI: 10.2174/1381612811319260007

Price: $65


Glycogen Synthase Kinase-3 (GSK-3) is a constitutively acting multifunctional serine/threonine kinase, a role of which has been marked in several physiological pathways, making it a potential target for the treatment of many diseases, including Type-II diabetes and Alzheimer’s. Design of GSK-3β selective inhibitor was the key challenge which led to the use of rational approaches like structure based methods (molecular docking), and ligand based methods (QSAR, pharmacophore mapping) studies. These methods provide insights into the enzyme–ligand interactions and structure activity relationship of different sets of compounds for the design of promising GSK-3 inhibitors. Molecular dynamic simulation studies have additionally been performed to address key issues like the unique requirement of prime phosphorylation of its substrate at P+4 by GSK-3β. An allosteric site has also been reported, where the binding of the peptide leads to the stabilization of the activation loop, resulting in the enhancement of the catalysis of enzymes. These studies are becoming useful in the design of therapeutically active discriminatory GSK-3 inhibitors. In this article, we present a review of recent efforts and future opportunities for the design of selective GSK-3β inhibitors.

Keywords: Glycogen synthase kinase-3, inhibitors design, rationale approaches, selectivity, type-ii diabetes, Alzheimer’s disease, ATP competitive inhibitors, Substrate competitive inhibitors.

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