Protein kinases are potential targets of drugs to treat many human diseases. Intensive efforts have been made to develop protein
kinase inhibitors, but a major challenge is achieving specificity. Exploiting regulatory elements outside the ATP binding pocket, such
as the substrate binding site, may provide an alternative that allows generation of competitive inhibitors with improved selectivity. Indepth
understanding of substrate recognition by protein kinase is essential for design and refinement of competitive inhibitors. Here we
described strategies for specifically targeting protein kinases and highlight our current progress in the development of substrate competitive
inhibitors for glycogen synthase kinase-3 (GSK-3).
Keywords: Protein kinase, GSK-3, substrate recognition, inhibitor design, substrate binding site, competitive inhibitors, selectivity, phosphorylation, Synthetic peptides, long-term treatment
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