Therefore, the traditional treatment of proteins as rigid structures is insufficient and often misleading for structure-guided drug screening and design. Docking ligands to their protein targets is particularly challenging when attempting to reproduce the binding mode of small molecules to ligand-free or alternative ligand-bound protein structures, which invariably occurs in the practical application of any docking method. Specifically, docking with ligand-bound (holo) protein structures typically leads to an accuracy of 60-80%, whereas ligand-free (apo) structures yields a docking accuracy of merely 20-40% .