• drug design;
  • glycogen synthesis kinase 3β;
  • molecular docking;
  • molecular dynamics simulations;
  • selectivity

Hymenialdisine and dibromocantharelline are marine sponge constituents with unique biological activity. Hymenialdisine potently inhibits glycogen synthase kinase 3β, cyclin-dependent kinase 2, and cyclin-dependent kinase 5, whereas dibromocantharelline only displays a significant inhibitory effect toward glycogen synthase kinase 3β (IC50 = 3 μmol). Based on the crystal structure of cyclin-dependent kinase 2–hymenialdisine complex, we employed three docking methods, namely Autodock, FlexX, and Genetic Optimization for Ligand Docking, as well as molecular dynamics simulations to investigate the structural determinants that govern target selectivity. The similar binding modes of hymenialdisine in complex with cyclin-dependent kinase 5 and glycogen synthase kinase 3β are consistent with the poor selectivity of hymenialdisine toward the two kinases. The shape of cyclin-dependent kinase 5 binding pocket characterized by the inward-orientation of Asp144 and dense electrostatic interaction networks, as well as the stereochemical configuration of dibromocantharelline, provides a considerable structural basis for the lack of binding of dibromocantharelline with cyclin-dependent kinase 5. The specific residue Cys199 near the binding site of glycogen synthase kinase 3β provides new clues for the design of potent and selective inhibitor of glycogen synthase kinase 3β.