The following two tables present the top 30 docking hits in the presence of the heme cofactor. In these cases, the intermolecular interactions are more complex because the ligand-protein and ligand-cofactor interactions are both crucial. Furthermore, when a natural product exhibits strong binding, it is likely underestimated because not only were the protein and ligand kept rigid, but the heme cofactor was also held in a fixed geometry and orientation relative to the protein-one that was optimal for the native ligand in the crystal structure. Consequently, local flexible geometry refinement with more advanced computational methods could enhance the apparent binding affinity of a given ligand even more significantly than in ligand-protein systems without the cofactor.