The co-crystal structures revealed, for instance, that the phenylene core of the best compound 30 (Figure , top) was situated in a perpendicular orientation to Tyr98 which is optimal for a Tshaped p-p interaction. The three methyl groups of 30 pointed into the solvent and were not engaged in specific interactions with the binding site of the protein, which might have affected the dihedral angles. Hence, the experimental dihedral angles around the phenylene connection to both the benzylic carbon (271°) and the thiazole carbon (60°) were very close to the calculated minima (Figure ). It could be concluded that this region of the ligand was optimally preorganized into a conformation which allowed for T-stacking with Tyr98 while maintaining the binding mode of the methylthiazole moiety (see also Figure , Figure ).