Biased library design

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). 

We call focused, or biased, or similarity based the libraries designed using structural information (a compound active on the target, or on a similar target) or a rational hypothesis and allowing the library structure to focus on very specific features. The main properties of such libraries are shown in Fig. 5.4. 

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-... 

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). 

Reagent-biased product design is now quite widely used and commonly the method of choice. " " The methods most commonly applied to measure diversity in large compounds sets (combinatorial libraries or screening collections) include 2D fingerprints (for substructural... 

Figure 7 Identification of GW 2433. The biased library comprised a biasing fibrate monomer at Rl. R2 and R3, derived from carboxylic acids and isocyanates, were chosen for diversity by means of experimental design techniques.

Akritopoulou-Zanze, I., Metz, J.T., and Djuric, S.W. (2007) Topography-biased compound library design the shape of things to come Drug Discovery Today,... 

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