Combinatorial synthesis Interactions

In the absence of any information about the structure of a target, combinatorial synthesis can be used to explore a set of diverse scaffolds that direct potential binding interactions to different angles and distances from each other. The structure-activity relationship that emerges from... 

Another use for combinatorial libraries has been the screening of peptides for antimicrobrial properties. In this case, the design of the library is based on antimicrobial peptides found in nature. A combinatorial synthesis is used to find alternative unnatural amino acids expected to mimic the antimicrobial properties.23 Peptide libraries also have been used to find compounds that could bind the lytic peptide mellitin.24 The library was synthesized in solution phase, purified, and evaluated using time-of-flight mass spectrometry (TOF-MS). The sequences determined to bind to mellitin contained hydrophobic pairs. By binding to mellitin, they were able to prevent the cell-surface mellitin interaction. This is an example of a peptide library able to afford compounds that interact with other small peptides without having to find an interacting protein first. 

Combinatorial Synthesis of Alkaloid-like Compounds In Search of Chemical Probes of Protein-Protein Interactions... 

JK Chen, SL Schreiber. Combinatorial synthesis and multidimensional NMR spectroscopy an approach to understanding protein-ligand interactions. Angew Chem Int Ed Eng 34 953-969, 1995. 

Examples in which solid-phase extraction has been applied to solution-phase combinatorial synthesis are listed in Table 3.12 for extraction by ionic interactions, and in Table 3.13 for extraction by covalent bond formation. 

Jennings LD, Foreman KW, Rush TS et al (2004) Combinatorial synthesis of substituted 3-(2-indolyl)piperidines and 2-phenyl indoles as inhibitors of ZipA-FtsZ interaction. Bioorg Med Chem 12 5115-5131... 

Tlie basic study of intermolecular interactions is facihtated by one-bead-one-stRicture libraries which can be powerful tools for the discovery of hgands to synthetic receptors and vice versa. Encoded combinatorial libraries have been useful for disclosing ligands for well-designed macrocyclic host molecules and to elucidate their specificities for peptide sequences. These studies led via receptors with more flexibility to simple host molecules without elaborate design that ai e accessible to combinatorial synthesis. One application is the development of chemical sensors for analytes that are otherwise difficult to detect or only non-specificaUy detected. Such hbraries have been used to find new catalysts and enzyme mimics. 

Solution-Phase Combinatorial Synthesis Boger et al. [71] constructed mixtures containing iminodiacetic acid diamides functionalized diamide precursors were dimerized by means of reactions with bis(tributylstarmyl)acetylene using (PhjPl Pd as the catalyst and butylated hydroxytoluene (BHT) as an additive to give product libraries suitable for probing protein-protein interactions. 

Figure 6 Reaction network based on the interaction of trideoxynucleotide derivatives Ap, Bp, nA, and nB to give four possible hexameric 3 -5 -phosphoramidates by combinatorial synthesis via autocatalytic (ApnB and BpnA) or cross-catalytic pathway (ApnA and BpnB).

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