Fig. 7.10 It was possible to soak small probe molecule (so-called “fragments”) into crystals of the protease thermolysin. (a) Superposition of multiple structures in which water (red spheres), isopropanol (C atoms are gray), acetone (C atoms are light blue), acetonitrile (C atoms are green), and phenol (C atoms are violet) had penetrated the crystals. They describe potential positions for functional groups of putative ligands. The structure of benzylsuccinic acid, a weakly binding inhibitor of thermolysin, is also shown in (b). That molecule coordinates with one of its acid groups to the catalytic zinc ion (upper row). Both oxygen atoms of the acid group displace two water molecules that are present in the non-complexed structure. The other carboxylate group forms a salt bridge with the neighboring Arg203. The oxygen of an acetone molecule was found at almost the same position. The phenyl ring of the benzylsuccinic acid that occupies nearly the same position as the phenol molecule in the fragment structure was detected. Benzylsuccinic acid can be used as a starting structure for further optimization.