Using an Enzyme's Active Site To Template Inhibitors This work was supported by the Centre National de la Recherche Scientifique and by the Ecole Polytechnique (predoctoral fellowship to R.N.). We thank Prof. Jean-Marie Lehn for stimulating discussions.

The identification of substances that have a strong affinity for the surface or the active site of a protein is not a trivial task. Numerous strategies can be followed, ranging from de novo design to the systematic screening of large libraries. One approach makes use of the recognition between the target protein and building block precursors to favor the formation of a complementary substance. Thus, materials capable of selectively recognizing protein surfaces may be prepared by using the molecular imprinting technique. The protein acts as a template to kinetically generate specific recognition sites in a polymer matrix, which is formed irreversibly.[1, 2] In a related approach, namely dynamic combinatorial chemistry, an enzyme s active site may template the assembly of a complementary substance from a mixture of interconverting species (Figure 1). In this case, the precursors combine through reversible linkages. Under thermodynamic conditions, the protein selects and stabilizes the products with the highest affinity,[3, 4] which leads to their amplification and hence their identification.