One of the main complicating factors in structure-based drug design is the conformational rearrangement of the receptor upon ligand binding implicating protein flexibility as a crucial component in virtual screening. The FlexE approach allows flexibility through discrete alternative conformations of varying parts of the protein taken from structures having similar backbone traces. Here the performance of FlexE was tested against that of FlexX and FlexX-Pharm, by carrying out virtual screening experiments on two sets of structurally distinct complexes, for the enzymes beta-secretase (BACE), and c-jun N-terminal kinase 3 (JNK-3). A large number of incompatible instances occurred between structural elements of the proteins thus loop movements could not be studied in JNK-3 as well as in BACE. The investigation of the side-chain flexibility revealed that at the most FlexE could achieve the enrichment yielded by FlexX in JNK-3 but not in BACE. Although limited side-chain variations (e.g. different protonation states) can be treated by FlexE, docking into protein ensembles remains a practical tool that decreases the average run time for a ligand.