UCLA

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 3β (GSK-3β) 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-3β 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-3β 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-3β 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-3β inhibitors based on other paradigms.