Dynamic Combinatorial Chemistry The Principle

Dynamic combinatorial chemistry (DCC) is a recent and rapidly developing approach for ligand or receptor identification, based on the implementation of dynamic assembly and recognition processes [10-20]. It offers a possible alternative to the static approaches of traditional combinatorial chemistry. The method is based on the generation of a dynamic combinatorial library (DCL) of interchangeable constituents. Such a DCL consists of continually interchanging library members generated by reversible reaction between a set of building blocks (components). The set of all potentially accessible self-assembly combinations of the components represents a virtual combinatorial library (VCL). The interaction of the library constituents with a molecular target drives the equilibrium towards the formation of those individual library members that bind to the target and thus are thermodynamically stabilized. Such a self-screening process, by which the active species are preferentially generated at the expense of the non-active ones and retrieved from the dynamic mixture, drastically simplifies the identification of effective ligands in the pool. The DCC approach is target-driven and combines two basic supramolecular themes [21]: self-assembly in generating a DCL and molecular recognition in the interaction of all possible entities with a target species.

The DCC concept is represented schematically in Fig. 16.1 using the "lock and key" image of Emil Fischer. The process can be divided into three simple steps: (a) selecting the initial building blocks, capable of connecting reversibly with each other, (b) establishing the library generation conditions, where the building blocks are allowed to form interchanging, individual molecular entities, and (c) subjecting the library to selection, in this case, binding affinity to a target species. If the target molecule acts as a trap for a good binder, the ensemble of candidates can be

Cem Combinatorial Chemistry

Schematic representation of the concept underlying dynamic combinatorial chemistry and virtual combinatorial chemistry based on the "lock and key" image of Emil Fischer.

Schematic representation of the concept underlying dynamic combinatorial chemistry and virtual combinatorial chemistry based on the "lock and key" image of Emil Fischer.

16.3 Generation of Diversity: DCC Reactions and Building Blocks | 343

forced to rearrange to favor the formation of this species. The process described where ligands are screened towards a given receptor is termed "substrate casting"; and the corresponding process where a synthetic receptor is selected by the addition of a certain ligand can is termed "receptor molding" [22].

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