Combinatorial loop

The main application field for HTE deals with the iterative process of library design and testing to find well-performing catalysts. Each step of the so-called combinatorial loop" (Fig. 10.1) will be presented, underlining the pros and cons that can arise from this new methodology. 

Fig. 10.3 Combinatorial loop for the evolutionary catalyst optimisation following Strategy WGS 1 [7, 11],...

The high-throughput production of data at each level of the combinatorial loop enforces an automated flow of data, which requires automated acquisition and retrieval. Since no database adapted to the specific case of heterogeneous catalysis is currently available (except those included in soft- and hardware packages provided by specialised companies, but at prices that academic groups cannot afford), the only solution was to develop an in-house database that fitted exactly the laboratory requirements. 

This chapter has tried to follow, step-by-step for a given case study, the pros and cons that may be revealed at each stage of the so-called combinatorial loop, using academic hard- and software tools. 

McNaughton, B. R. Gareiss, P. C. Miller, B. L. Identification of a selective small-molecule ligand for HlV-l frameshift-inducing stem-loop RNA from an 11,325 member resin bound dynamoic combinatorial library. J. Am. Chem. Soc., 2007,129, 11306-11307. 

Branching and crosslinking processes can be treated as a combinatorial problem which is not too complicated when the functionalities are equally reactive and unreacted functionalities are considered as the only kind of defects. If loop formation (intra-molecular cyclization) is involved, the complexity increases considerably. The same holds if the monomers contain groups of unequal reactivity or if the reactivity is influenced by substitution effects. 

Fig. 10.1 Basic principle of the combinatorial approach applied to catalysis iterative loop up to achievement of new product or process specification.

In Section II.C we will present novel tricyclic xanthene derived amino acid templates, which allow the construction of libraries of cyclic conformationally constrained peptide loop mimetics using the split-and-mix method without having to use tagging and deconvolution strategies. In Section III we will focus on parallel and combinatorial approaches devoted to the synthesis of small molecule, non-peptidic compound collections, which in addition offer the possibility to incorporate structural features derived from protein epitope mapping into conformationally constrained peptide mimetics. 

---