Biased Libraries

As mentioned above, in order to avoid creating severely biased libraries, components of comparable reactivity should be used in the library construction. Due to slow exchange rates or unfavorable equilibria, some thiols and acyl components were excluded from further studies. However,... 

Synthetic library Naive library Antigen-biased library... 

Trask, O.J., Jr. et al. 2006. Assay development and case history of a 32K-biased library high-content MK2-EGFP translocation screen to identify p38 mitogen-activated protein kinase inhibitors on the Array Scan 3.1 imaging platform. Meth. Enzymol. 414, 419-439. 

In parallel, hits are nominated from the group of actives, and chemical optimization is begun, to generate optimized leads. Ideally, the biased library consists of lead-like compounds and allows an efficient, short optimization program. We can anticipate that this parallel approach in chemical biology will lead to time reduction by 3.5 years as compared to the classical linear approach. 

A primary, or unbiased, library is a large set of compounds (t5q)ically thousands to millions) based on diversity and aimed at the discovery of samples of interest for targets for which little, if any, information is available. Diversity is a concept unrelated to the library size that attempts to evaluate the representation of chemical space by a chemical library using computational methods If this space is sampled evenly by the components of a library, then this library is considered to be diversity based (Fig. 4.1, left). A focused, or biased, library is a similarity-based set of compounds (typically hundreds to thousands) aimed at the discovery and optimization of lead structures for a target for which a structural model on which to design the hbrary is available. Similarity is a concept unrelated to the library size that is opposite to diversity if the library components are clustered around the model structure A, the library is similarity based (see Fig. 4.1, right). 

A more complex combinatorial strategy based on a natural scaffold was reported by Nicolaou et al. (56) with the synthesis of an epothilone-based SP library L27 (Fig. 4.18). This biased library was prepared asa3x3x5 = 45-member collection, but the final reaction vessels could, theoretically contain 4 different isomeric desoxyepothi-lones (Fig. 4.18), thus leading to a total number of 45 x 4 = 180 components. The library was prepared using a radiofrequency encoding technique (42), and the final... 

An example of a biased library, shown in Fig. 5.7, which was reported by Boger et al. (10), was designed to be a source of tools to probe protein-protein interactions (why). The effort required for the chemical assessment and for a satisfactory charac-... 

Schreiber and co-workers recentiy reported (134, 135) the synthesis of two SP pool libraries L3 and L4 based on the structmes of a phage display-derived dodecapeptide ligand of the SH3 domain of the tyrosine kinase Src (7.14, Fig. 7.13) (136), of its truncated version (7.15), and of a nonpeptide ligand derived from an encoded primary library (7.16, Fig. 7.13) (137). The authors kept the common motif proline-leucine-proline (PEP) in the biased library structmes and explored the left (library L3, 2500 members. Fig. 7.13) and the right part of the ligand sequences (library L4, 125,000... 

Figure 7.42 SP chemistry assessment for the large, natural products-biased library L12 compounds 7.82a-c and 7.83a-c.

Figure 7.44 SP synthesis of the natural products-biased library model library Lll.

A further key advantage of NMR is its ability to provide additional stractural information, which is welcome even at the earliest stages of the drug development process. Structural information supports rational lead design or the design of biased libraries based on known structure activity relationships (SARs). 

A third revelation was that there were some common problems, for example, the toxicity of lead compounds against kinase targets or the need to develop biased libraries of compounds to enhance hit finding or lack of structural information about the specific kinase enzymes. 

---