Protein　kinase　is　a　novel　therapeutic　target　for　human　diseases.　The　off-target　and　side　effects　of　ATP-competitive　inhibitors　preclude　them　from　the　clinically　relevant　drugs.　The　compounds　targeting　the　druggable　allosteric　sites　outside　the　highly　conversed　ATP　binding　pocket　have　been　identified　as　promising　alternatives　to　overcome　current　barriers　of　ATP-competitive　inhibitors.　By　simultaneously　interacting　with　the　D　region　(new　allosteric　site)　and　sub-ATP　binding　pocket,　the　attractive　compound　CAM4066　was　named　as　allosteric　inhibitor　of　CK2.　It　has　been　demonstrated　that　the　rigid　linker　and　non-ionizable　substituted　fragment　resulted　in　significant　decreased　inhibitory　activities　of　compounds.　The　molecular　dynamics　simulations　and　energy　analysis　revealed　that　the　appropriate　coupling　between　the　linker　and　pharmacophore　fragments　were　essential　for　binding　of　CAM4066　with　CK2.　The　lower　flexible　linker　of　compound　21　lost　the　capability　of　coupling　fragments　A　and　B　to　D　region　and　positive　area,　respectively,　whereas　the　methyl　benzoate　of　fragment　B　induced　the　re-orientated　Pre-CAM4066　with　the　inappropriate　polar　interactions.　Most　importantly,　the　match　between　the　optimized　linker　and　pharmacophore　fragments　is　the　challenging　work　of　fragment-linking　based　drug　design.　These　results　provide　rational　clues　to　further　structural　modification　and　development　of　highly　potent　allosteric　inhibitors　of　CK2.