Chemical diversity as a driving force to design and put in practice synthetic strategies leading to combinatorial libraries for lead discovery and lead optimization

Publisher Summary This chapter discusses the chemical diversity as a driving force to design and put in practice synthetic strategies leading to combinatorial libraries for lead discovery and lead optimization. Target identification and target validation are now crucial milestones, as the unraveling of the human genome is providing thousands of new, uncharacterized genes as potential targets for the cure of important diseases. Research laboratories able to identify and validate targets better and faster than competitors will be significantly advantaged, and combinatorial approaches and tools will provide relevant benefits at this stage. The full potential of chemical diversity and combinatorial libraries is evident in the following three steps of the process, that is, (1) from target to hit; (2) from hit to lead; and (3) from lead to clinical candidate. Once a target is validated, the hit identification phase kicks off and chemical disciplines start to be heavily involved. While biologists develop a suitable biological assay to identify compounds interacting with the target, chemists will assemble a suitable chemical collection (diversity), which is screened on the biological assay (screening) eventually leading to active compounds, or hits (structure determination). If the target is novel and poorly characterized, chemical diversity is the main driver to assemble a screening collection. A collection spanning the so-called diversity space is more likely to identify an active compound, or hit, than a collection that is clustered in an area of the same space.

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