Combinatorial libraries: studies in molecular recognition

In recent years, combinatorial libraries have become a major tool for drug discovery and drug development. Along the way, one potential use of combinatorial chemistry libraries almost been neglected: the basic study of intermolecular interactions. Especially "one-bead-one-structure" libraries can be a powerful means for the discovery of ligands to synthetic receptors and vice versa. Encoded combinatorial libraries have been used to disclose ligands for well designed macrocyclic host molecules and to elucidate their specificities for peptide sequences. These studies led via receptors with more flexibility to simple host molecules without elaborate design that are accessible to combinatorial synthesis. These findings open a realm of possibilities and applications. An intriguing one is the development of chemical sensors for analytes that are otherwise hard or only unspecifically detected. Furthermore, such libraries and the techniques that were developed to handle them have been used to find new catalysts and enzyme mimics. In this review we put the emphasis on studies involving "one-bead-one-structure" libraries. We will review the techniques to generate them, to encode and analyze them, and to assay them. We will describe their past usage and the intriguing results of these studies and point out interesting new applications of such libraries for the study of non-covalent intermolecular interactions.