Combinatorial chemistry for the generation of molecular diversity and the discovery of bioactive leads

The principles of the combinatorial synthesis of large compound libraries are described. It is shown that these technologies can afford unprecedented numbers of chemical entities thus increasing the molecular diversity of the universe of organic compounds. Library design is considered in view of the generation of a maximized diversity for a given set of synthetic products. The advantages of solid phase organic chemistry are stressed and compared to the achievements of solution procedures for the production of large compound collections. The trend from the truly combinatorial synthesis of millions of biooligomers towards the parallel synthesis of individual small organics is stated and exemplified. Finally, an overview is given of the methods developed for the structural identification of the active component(s) in compound libraries and arrays, including iterative deconvolution via re-synthesis, positional scanning or structural analysis of the ligand on a single polymer bead. Strategies are suggested for both lead discovery and lead optimization.