Docking and structure activity relationship studies of potent and selective thiazolidinethione GSK-3 inhibitors

[Display omitted] •A series of GSK-3 inhibitors were prepared and screened for their GSK-3 inhibitory activity.•A preliminary structure activity relationship was observed.•Docking studies were carried out to identify key components of the highly specific interactions of the inhibitors with GSK-3. Glycogen synthase kinase-3 (GSK-3) plays a key role in several biochemical pathways and is an attractive target for pharmacological intervention. We prepared a series of analogs of a highly selective thiazolidinethione inhibitor of GSK-3. The structure–activity relationship indicated a precise structural requirement for potent inhibition. We used docking and bioinformatic analysis to explore the rationale for the potency and selectivity of this class of GSK-3 inhibitors. These computational studies identified residues unique to GSK-3 likely to play a role in ligand-specific induced fit interactions. Together, these studies highlight the structural stringency of specific kinase inhibition that can be achieved for GSK-3.