Contrasting Effects of Inhibitors Li+ and Be2+ on Catalytic Cycle of Glycogen Synthase Kinase-3β

Ionic lithium shows rare effectiveness for treating bipolar disorder and is a potential drug for neurodegenerative diseases. Unfortunately, lithium suffers from significant drawbacks, mainly a narrow therapeutic window. Among the targets of lithium, glycogen synthase kinase 3 beta (GSK-3 beta) may be responsible for its therapeutic effects. The development of alternative, selective inhibitors of this kinase could prevent lithium side effects, but such efforts have met little success so far. An atomistic understanding of Li+ inhibition and the GSK-3 beta phosphorylation reaction would therefore facilitate the development of new drugs. In this study, we use extensive sampling of catalytic states with our mixed quantum-classical dynamics method QM/DMD and binding affinities from a competitive metal affinity (CMA) approach to expand the atomistic picture of Li+ GSK-3 beta inhibition. We compare Li+ action with Be2+ and find our results in agreement with in vitro kinetics studies. Ultimately, our simulations show that Li+ inhibition is driven by decreasing the phosphorylation reaction rate, rather than reducing catalytic turnover through tight binding to different GSK-3 beta states like Be2+ inhibition. The effect of these metals derive from electrostatic differences and especially their smaller atomic radii compared to the native Mg2+ and thus provide insight for the development of GSK-3 beta inhibitors based on other paradigms.

Automated summary

This study expands the atomistic picture of Li+ GSK-3β inhibition using quantum-classical dynamics and competitive metal affinity approaches, finding that Li+ inhibition is mainly driven by decreasing the phosphorylation reaction rate. Compared to Be2+ inhibition, Li+ inhibition relies more on electrostatic differences and smaller atomic radii.