Fig. 25.5 The 3D structure of a complex of thermolysin and Cbz–GlyP –Leu–Leu 25.4 (gray carbon atoms). The leucine side chain (right) neighboring a phosphate group occupies the deep S1′ pocket that is pointed toward the interior of the protein; the second leucine residue lies in the shallow S2′ pocket that is open to the surface. The Cbz group is oriented in the S1 pocket (left). The macrocyclic inhibitor 25.5 (green carbon atoms) with the chromane scaffold locks the conformation of 25.4 and places the leucine side chains in S1′ and S2′ in an analogous way. Although this inhibitor leaves the S1 pocket completely unoccupied, it binds to thermolysin more strongly than the open-chain compound 25.4.