Identifying Potential Ligand Binding Sites on Glycogen Synthase Kinase 3 Using Atomistic Cosolvent Simulations

Glycogen synthase kinase 3 β (GSK3β) is a serine/threonine kinase that phosphorylates several protein substrates in crucial cell signaling pathways. Owing to its therapeutic importance, there is a need to develop GSK3β inhibitors with high specificity and potency. One approach is to find small molecules that can allosterically bind to the GSK3β protein surface. We have employed fully atomistic mixed-solvent molecular dynamics (MixMD) simulations to identify three plausible allosteric sites on GSK3β that can facilitate the search for allosteric inhibitors. Our MixMD simulations narrow down the allosteric sites to precise regions on the GSK3β surface, thereby improving upon the previous predictions of the locations of these sites.