In the case of compound 37, which was weaker binder than 33 and 30 (Table ), the Tstacking interaction was completely lost due to the inherent rigidity of the bicyclic ring system (Figure , bottom). In addition, the planes of the methylthiazole and the aromatic core were almost coplanar and the dihedral angle of 15° was calculated to be extremely energetically unfavorable (Figure ). This data emphasized the importance of the interaction with Tyr98 and the advantages that can be gained by preorganizing the protein-bound ligand in a lowenergy conformation that is compatible with optimal protein-ligand interactions.