Hymenialdisine　and　dibromocantharelline　are　marine　sponge　constituents　with　unique　biological　activity.　Hymenialdisine　potently　inhibits　glycogen　synthase　kinase　3　beta,　cyclin-dependent　kinase　2,　and　cyclin-dependent　kinase　5,　whereas　dibromocantharelline　only　displays　a　significant　inhibitory　effect　toward　glycogen　synthase　kinase　3　beta　(IC50　=　3　mu　mol).　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　3　beta　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　3　beta　provides　new　clues　for　the　design　of　potent　and　selective　inhibitor　of　glycogen　synthase　kinase　3　beta.