Identifying the Cellular Targets of Bioactive Small Molecules with Activity-Based Probes

The renaissance of cell- or organism-based phenotypic assays has made subsequent target identification for bioactive small organic molecules an important aspect of current drug discovery. Among the many strategies available for target identification, derivatizing bioactive small molecules into activity-based probes has the main advantage of determining small molecule-protein interactions directly in the native environment where the target proteins maintain their three-dimensional structures, including all the post-translational modifications, as the discrete small molecular probes usually have better access to intracellular compartments. Thus this chemical platform will not only afford a more precise means of understanding the mechanisms of action for bioactive molecules, but shed light onto the specificity of the bioactive small molecules. Here we will provide an overview of the strategies for the design of activity-based small molecular probes and review their applications for target identification using case studies. Special emphasis is placed on logistic concerns for probe's design as well as recent developments in this field.