Perspectives in Pharmacology Ligand Discovery Using Small Molecule Microarrays

Small molecule microarrays have recently been used to identify ligands for several proteins, and several themes regarding screening strategies and limitations have emerged. In this review, some of the technical issues related to the manufacture and screening of small molecule microarrays, as well as prospects for small molecule microarrays in several areas of drug discovery and chemistry, are discussed. A major advance in drug discovery has been the development of techniques to generate large libraries of chemical compounds using combinatorial chemistry. Several combinatorial chemistry techniques exist to generate large libraries, including the split-pool (or “one bead-one compound”) approach. These techniques have increased the number of compounds that are available for screening purposes. However, with the large number of different types of libraries available, methods to rapidly screen these libraries for molecules that have biologically relevant activity are needed. In this review, we will discuss one new approach for improving library screening—the small molecule microarray. In this review, we will use the term “small molecule” to refer to nonDNA molecules that are prepared using synthetic chemistry, rather than molecules that are obtained from cells or biochemical reactions, such as proteins. The small molecule microarray is a library of compounds that is immobilized on a two-dimensional surface, such as a glass slide, and is spatially addressable and miniaturized. Small molecule microarrays have recently been used to identify ligands for several proteins, and several themes regarding screening strategies and limitations have emerged. In this review, we will discuss the manufacture and use of microarrays as well as its potential for contributing to the lead identification process. We will also discuss prospects for small molecule microarrays in other areas of drug discovery and chemistry. Historical Foundation of Small Molecule Microarrays