Update on ChemMine

Chemical genomics is a promising new technology for studying gene functions in the context of living organisms or cell systems. It complements existing molecular and genetics tools (e.g. mutagenesis, RNAi) by allowing fine-tunable in vivo modulations of protein functions and cellular processes (Blackwell and Zhao, 2003; Austin et al., 2004; Lipinski and Hopkins, 2004). This approach is feasible because of recent advances in the synthesis of large libraries of small chemicals. In chemical genomics experiments the libraries are used to identify in high-throughput screens interesting agonistic or antagonistic candidates that interfere with a biological process of interest. Typically, the libraries, used in these screens, consist of collections of diverse compounds with predicted drug-like properties (Lipinski et al., 1997; Oprea and Gottfries, 2001; Oprea, 2002; Baurin et al., 2004; Stockwell, 2004). In analogy to genetic screens, chemical genomic screens can utilize forward and reverse strategies (Schreiber, 1998; Haggarty et al., 2003). Forward chemical genomics screens probe modulations of complex biological processes rather than isolated targets. This is in contrast to small molecule discovery in the pharmaceutical and agricultural industry where the drug-able target is usually known and screened using in vitro systems. To fully understand the mode of action of isolated compounds with interesting biological activities, it is frequently necessary to identify their target(s) at a later stage of a screening project using biochemical and genetics gene or protein isolation techniques. In contrast to this forward strategy, reverse chemical genomics screens resemble, in their initial stage, drug discovery approaches by screening known targets (Drews, 2000). Subsequently, the isolated bioactive chemicals are used to study the molecular and biological functions of poorly characterized proteins in vivo. Both forward and reverse approaches utilize the identified chemicals as ‘‘research tools’’ for determining the functions, interactions, and architecture of cellular networks in living organisms. A potential pharmaceutical or agricultural application can be of interest but is not the central goal of this technology. Chemical genomics has several outstanding advantages over classical genetics and molecular techniques for studying gene functions. Standard genetics approaches target one gene at a time and provide limited opportunity to control the extent of the downstream cellular effects. By contrast, chemicals can be targeted with spatiotemporal precision against a selected spectrum of proteins. They can be applied in defined dosages to distinct cells, organs, or developmental stages, often with rapid response times and reversible effects. Since chemical switches can act in a similar manner across a range of model or nonmodel organisms, their identification is of great interest for researchers working with different model systems. Finally, the chemicals can be used to inactivate a family of proteins with related sequences or structures in a single step. In the future, these ‘‘chemical family knock-downs’’ may be the method of choice for the functional characterization of paralogous genes with redundant functions.