Libraries focused

4 Focused libraries. A basic idea behind the design of diverse libraries has been that representative coverage of global chemically diversity would ensure that libraries could produce hits against many different therapeutic targets and thus be 

Besides the established sources of obtaining diversity, mainly from historic compound collections, publicly or commercially available compound libraries, and natural products, novel approaches toward expanding diversity have been described in the recent literature. 

The notion that compounds with a benzodiazepine core were active as ligands against a variety of GPCRs, such as central and peripheral benzodiazepine, kappa opioid, and CCK receptors, has led to the privileged structure concept [84]. The observed activity crossover of a single compound to multiple targets of the same 

The authors noted that while this approach worked well in designing active molecules, it remains to be challenging to also find selective kinase inhibitors [87]. 

A similar virtual fragment linking approach validated across a variety of different target classes has also been reported [88]. A combination of virtual and experimental (NMR, biochemical) screening methods was employed to identify novel scaffolds for the design of kinase-targeted libraries [89]. 

Compared to ligand-based approaches, the use of structure-based methods has received less attention in the past, mainly due to their limited applicability to target classes with available protein structures and also because some of the methods such as docking still involve computationally intensive processes. Nevertheless, for 

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Fig. 3-7. Evaluation of a focused library of 71 DNB-dipeptide CSPs for enantioseparation of the test racemate 8. (Reprinted with permission from ref. [86], Copyright 1999, American Chemical Society.)...

Screening of derivatives of these compounds, optional a synthesis of a focused library yielding such derivatives to obtain compounds with improved affinity. 

Detection of the affinity of the new compound and further improvement by synthesis of focused library on the basis of the design. 

CombiGlide A combinatorial version of the Glide algorithm which can be used for the design of focused libraries Schrodinger, Inc. http //www.schrodinger.com [34]... 

To date, many of the reported ADME/Tox models have been rule based. For example, some research groups have used relatively simple filters like the rule of 5 [93] and others [94] to limit the types of molecules evaluated with in silico methods and to focus libraries for HTS. However, being designed as rapid computational alert tools aimed at a single property of interest, they cannot offer a comprehensive picture when it comes to understanding ADME properties. 

The issue of parallel versus sequential synthesis using multimode or monomode cavities, respectively, deserves special comment. While the parallel set-up allows for a considerably higher throughput achievable in the relatively short timeframe of a microwave-enhanced chemical reaction, the individual control over each reaction vessel in terms of reaction temperature/pressure is limited. In the parallel mode, all reaction vessels are exposed to the same irradiation conditions. In order to ensure similar temperatures in each vessel, the same volume of the identical solvent should be used in each reaction vessel because of the dielectric properties involved [86]. As an alternative to parallel processing, the automated sequential synthesis of libraries can be a viable strategy if small focused libraries (20-200 compounds) need to be prepared. Irradiating each individual reaction vessel separately gives better control over the reaction parameters and allows for the rapid optimization of reaction conditions. For the preparation of relatively small libraries, where delicate chemistries are to be performed, the sequential format may be preferable. This is discussed in more detail in Chapter 5. 

Barbosa, F., Mao, B., Revah, F. and Froloff, N. (2005) QSAR strategy and experimental validation for the development of a GPCR focused library. QSAR and Combinatorial Science, 24, 508-516. 

Jimonet, P. and Jager, R. (2004) Strategies for designing GPCR-focused libraries and screening sets. Current Opinion in Drug Discovery el Development, 7, 325-333. 

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