Diverse compound libraries

The requirement for diverse compound libraries by means of solid-phase synthesis led to the development of hnkers for most functional groups found in organic synthesis. The number of hnkers developed for a specific group also reflects the distribution of pharmacophoric groups present in natural products and other bioactive compounds. Tab. 3.16 gives an overview of examples of hnkers for different functional groups. 

Advances in chemical synthesis have enabled considerable sophistication in the construction of diverse compound libraries to probe protein function [61, 62). However, few general techniques exist that can directly assess binding mechanisms and evaluate ligand afEnities in a multiplexed format. To realize the full potential of combinatorial chemistry in the drug discovery process, generic and efficient tools must be applied that combine mixture-based techniques to characterize protein-ligand interactions with the strengths of diversity-oriented chemical synthesis. 

Combinatorial chemistry is both the philosophical and the practical method with which to create structurally diverse compound libraries. Combinatorial chemistry is defined as that branch of synthetic organic chemistry that enables the concomitant synthesis of large numbers of chemical variants in such a manner as to permit their evaluation, isolation, and identification. Combinatorial chemistry affords techniques for the systematic creation of large but structurally diverse libraries. From a technical perspective, there are several avenues of approach to library creation ... 

Figure 1.4. Examples of diverse and non-diverse compound libraries.

One type of oligoamide that can readily be prepared on supports without the need for any partially protected monomers (which are often tedious and expensive to synthesize) are N-substituted oligoglycines (Figure 16.21). These compounds are prepared by a sequence of acylation of a support-bound amine with bromoacetic acid, displacement of the bromide with a primary aliphatic or aromatic amine, and repeated acylation with bromoacetic acid. Because primary amines are cheap and available in large number, this approach enables the cost-efficient production of large, diverse compound libraries. Alternatively, protected N-substituted glycines can also be prepared in solution and then assembled on insoluble supports (Entry 5, Table 16.2). 

Functionalization during the cleavage process is an attractive objective for the generation of diverse compound libraries. 

An optimally diverse compound library for biological random screening would be a collection of representatives from a variety of compound clusters of similar molecules. Thus, the first step is to cluster molecules according to their similarity and composing afterwards a diverse set. The central task to solve this problem, for all kinds of molecules, is the identification of suitable molecular descriptors. 

The major tool for druggability profiling is a rapid, uniform, high-throughput binding assay with a large, diverse compound library, often with small molecule microarrays. 

Ma C, Lazo JS, Xie X-Q (2011) Compound acquisition and prioritization algorithm for constructing structurally diverse compound libraries. ACS Comb Sci 13 223-231... 

Preparative HPLC has been widely used for purification of peptides and small molecules for over a decade. Its inherent serial nature, lack of automation, and severe throughput limits, would seem to make it unsuitable for purification of large and diverse compound libraries. Recent advances in automation, detection, and method development, however, now make it possible to purify hundreds of compounds per day using a single instrument. Further throughput improvements may come from parallel HPLC systems which have been recently reported. 

Facile access to complex natural products and diverse compound libraries remains a central challenge in organic synthesis. 

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