Abstract
Chemical genetics is an approach for identifying small molecules with the ability to induce a biological phenotype or to interact with a particular gene product, and it is an emerging tool for lead generation in drug discovery. Accordingly, there is a need for efficient and versatile synthetic processes capable of generating complex and diverse molecular libraries, and Diversity-Oriented Synthesis (DOS) of small molecules is the concept of choice to give access to new chemotypes with high chemical diversity. In this review, the combination of chemical genetics and diversity-oriented synthesis to identify new chemotypes as hit compounds in chemical biology and drug discovery is reported, giving an overview of basic concepts and selected case studies.
Highlights
Drug discovery is a key field of pharmaceutical industries
Forward chemical genetics is the most attractive and the most used approach in chemical biology, because it allows for the discovery of both new targets and new lead compounds with potential therapeutic applications [7,8,9]
Diversity-Oriented Synthesis (DOS) [25,26], which aims to synthesize the largest number of structurally complex small molecules, was conceived as a novel concept for the construction of libraries mainly addressing drug discovery issues
Summary
Drug discovery is a key field of pharmaceutical industries. After an impressive growth at the end of the last century, the number of new molecular entities launched on the market dramatically decreased in recent years, so that it has been claiming that the “ice age” of drug discovery is approaching [1]. Target-based drug discovery approach remains the “gold standard” in hit identification, a fundamental challenge has emerged. In forward chemical genetics, a small molecule eliciting a desired phenotype is identified, and its protein partner is discovered subsequently following a deconvolution method. These studies (from molecule to protein to phenotype) are exploited when the aim of the investigation is the identification of molecules able to induce a specific biological effect. Reverse chemical genetics approaches are fundamental to validate a known target These studies involve functional small-molecule assays targeted directly to a protein of interest. Forward chemical genetics is the most attractive and the most used approach in chemical biology, because it allows for the discovery of both new targets and new lead compounds with potential therapeutic applications [7,8,9]
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