Library of libraries: A novel approach in synthetic combinatorial libraries

There are two types of library-based screening for new pharmacologically important leads: parallel and iterative (for the review of library techniques see e.g. [1,2]). The parallel approach is based on the principle of generating the complete, or as complete as possible, multiplicity of unique structures in a single library, which is then screened to identify the solid phase supports on which active compounds were synthesized. The compositions of the positive test compounds are then determined from information on the solid phase support. Since the number of unique compounds which must be synthesized to obtain a complete library increases exponentially, synthesis of complete libraries longer than pentapeptide is becoming impractical. This is the main disadvantage of the parallel approach. On the other hand it is accepted that in a long peptide not all amino acid residues are equally important for activity and only certain residues at certain positions (motif) are critical. Consequently it is not necessary to synthesize all possible structures, but instead to synthesize only compounds containing all possible motifs but not all structures sharing the same motif. For a particular target it is impossible to predict a priori how many residues are important for activity and how many residues must be defined in order to observe activity in a particular screening assay. In the iterative approach to the combinatorial libraries a number of libraries are synthesized, each initially containing one or two sequencial positions which are defined, with the remaining positions completely randomized. The most active library in a particular biological test is selected, beginning an iterative process of synthesis and screening of additional libraries until all portions of the active molecule are defined. In other words, the first step of the iterative process consists of screening libraries with very short motifs containing only one or two sequencia! residues. The "Library of Libraries" (library of motifs) approach is a powerful symbiosis of both approaches: parallel and iterative. To generate a single