Chemical Genetics

Small-molecule inhibitors are typically identified through high-throughput screening of large libraries of chemical compounds. These screens can be "target-specific," for example, when utilizing purified preparations of the targeted protein, or "phenotypic," when compounds are tested in more complex biological systems. This latter approach is often referred to as "chemical genetics," based on an analogy to traditional genetics. Traditional forward genetics seeks to link biological phenotypes identified in screens with mutations in specific genes. In forward chemical genetic screens, compounds are screened for their ability to produce a phenotype of interest without regard to the specific target. Subsequent identification of the protein targeted by the small molecule thereby causally links the small-molecule target with the biological process under study. Thus, phenotypic chemical genetic screens, like traditional genetic screens, can be used to elucidate molecular mechanisms through the identification of proteins essential for a biological process. In addition to providing a means to discover proteins, however, this approach also identifies corresponding chemical inhibitors that can be used to elucidate protein function. For example, the compound secramine was identified in a phenotypic screen for compounds inhibiting trafficking of the vesicular stomatitis virus G protein from the Golgi to the plasma membrane (Pelish et al. 2001). Subsequent identification of the target of secramine as the Rho GTPase Cdc42 thereby linked Cdc42 to vesicular trafficking from the Golgi and provided a novel reagent for studying this function of Cdc42 (Pelish et al. 2006).

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