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While potentially very powerful, affinity separation using tethered ligands has serious drawbacks. First, the ligand in question must be amenable to chemical coupling to solid support resins. Not all candidate compounds have the functional groups necessary to perform the requisite chemistry. Further, steric hindrance may preclude receptor binding and the altered spatial relationships may affect the ligand binding affinity and kinetics. Finally, the cellular fraction to be employed must be carefully prepared to ensure that the receptor retains function. This is not always possible, particularly for membrane-bound proteins. Nevertheless, in planning a strategy this approach should be explored as it could lead directly to target identification.