Introduction

Chemical genetics describes the use of molecules as “chemical probes” to investigate biological systems [1–3]. In contrast with traditional genetics, in which gene knockouts on the level of the DNA are used, chemical genetics uses biologically active small molecules to directly attenuate the corresponding biological macromolecular (usually protein) product. Thus, the ready availability of bioactive small molecules is of crucial importance in chemical genetics studies. Such small molecules can be identified by screening compound collections (libraries) in suitably designed assays. This chapter describes the use of diversity-oriented synthesis (DOS) to prepare structurally diverse small molecule libraries. Structurally diverse libraries show a greater variety in not only their physiochemical properties but also, and of most relevance here, in their biological activities. Herein we describe some of the most effective strategies that have been used in DOS library design and preparation.

Small molecules, chemical genetics, and chemical genomics

Chemical genetics experiments can be performed in either a forward or a reverse sense (Figure 4.1). The first step of both approaches requires the identification of a small molecule that either induces a desired phenotype (forward chemical genetics) or modulates the function of a specific protein of interest (reverse chemical genetics). Thus, in the former case, investigations proceed from phenotype to protein, whereas in the latter case, investigations progress from protein to phenotype.