Combinatorial libraries, target-specific

Substructure searches provide another method of searching for available starting materials. They arc used primarily for planning the synthesis of combinatorial libraries. After the target compound has been dissected into a set of suitable precursors, substructure searches can provide for each of them a series of representatives of a certain class of compounds, Siibsti ucturc searches enable the user to specify attributes such as open sites or atom lists at certain positions of the structure. Figure 10.3-38 shows the possible specification elements for the query in a substructure search. 

The observed differences create a basis for a rational selection of building blocks for synthesis of combinatorial libraries enriched in target-specific motifs. The quantitative structure-activity discrimination function found at this stage of our study can be used for effective search of reactive monomers possessing the desired physicochemical and spatial parameters. 

Fig. 12.8 Ge neral procedures of selection of a rational target-specific subset within an initial virtual combinatorial library.

In this paper, we elucidated some theoretical and practical aspects in the design of target-specific combinatorial libraries. In the studies we described to illustrate a real... 

Fig. 10.6 Concept of multitarget affinity specificity screening (MASS). Macromolecular targets (typically structured RNA constructs or proteins) in nondenaturing buffers are mixed in solution with a collection of potential ligands derived from natural product fractions, combinatorial libraries, or other diverse compound collections. The...

More recently, the focus has moved from diversity in favor of combinatorial libraries designed to target specific receptors or enzymes (12). While these single-target-focused libraries remain a key component of many drug-discovery programs, and are useful in both hit to lead and lead optimization contexts,... 

It is not hard to predict that with the output of genomics and proteomics, the number of proteins that can be related to specific diseases will increase tremendously in the next few years. Therefore methods that are able to screen combinatorial libraries in the search for interacting drugs are desperately required. Furthermore, efforts to re-examine known drugs for potential interactions with newly identified target proteins will increase, because it lowers costs considerably if a drug that has already passed the regulatory procedures can also be applied to cure a further disease. 

In 1991, we first introduced the one-bead one-compound (OBOC ) combinatorial library method.1 Since then, it has been successfully applied to the identification of ligands for a large number of biological targets.2,3 Using well-established on-bead binding or functional assays, the OBOC method is highly efficient and practical. A random library of millions of beads can be rapidly screened in parallel for a specific acceptor molecule (receptor, antibody, enzyme, virus, etc.). The amount of acceptor needed is minute compared to solution phase assay in microtiter plates. The positive beads with active compounds are easily isolated and subjected to structural determination. For peptides that contain natural amino acids and have a free N-terminus, we routinely use an automatic protein sequencer with Edman chemistry, which converts each a-amino acid sequentially to its phenylthiohydantoin (PTH) derivatives, to determine the structure of peptide on the positive beads. 

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