Combinatorial chemistry library development

Practising combinatorial chemistry enables companies to produce thousands of potential leads for a fraction of the cost of producing the same number of leads by traditional chemistry. This is probably why so many companies, in excess of 180, are involved in the field. These companies can be divided into four major categories, depending on their use of combinatorial chemistry—library makers, library value-adders, library users and finally hardware/software developers. The industry is, therefore, fragmented with no clear leadership position enjoyed by any single company. This also probably accounts for why the field is so rich in alliances and collaborations, whose value exceeds a few billion dollars and which occur among at least 130 of the 180 companies involved in combinatorial chemistry. 

This chapter has reviewed the basic principles of computer-aided drug design, and several strategies of how it can be successfully integrated with combinatorial chemistry to develop highly effective site-focused libraries. Diversity plays a key role, as the more diverse set of compounds tested that fit the site-focused criteria, the more information is retrieved to improve the site-focused definition, which further directs the search in diversity space. In addition, if good hits are found, the information can be fed back to find compounds close in diverse space to the hit. This new paradigm for structure-based combinatorial chemistry should provide a powerful tool for rapid discovery of novel, potent lead compounds in the years to come. 

To assess the quality of a combinatorial chemistry library, it is essential to determine the purity and quantity of the expected products. Commercial software, developed by instrument manufacturers, has made possible the unattended and rapid analysis of tens of thousands of individual components of a specific library. The application of LC/MS in high-throughput screening of combinatorial libraries has been reviewed by several authors [72-78]. 

In combinatorial chemistry, the development of multicomponent reactions leading to product formation is an attractive strategy because relatively complex molecules can be assembled with fewer steps and in shorter periods. For example, the Ugi multicomponent reaction involving the combination of an isocyanide, an aldehyde, an amine, and a carboxylic acid results in the synthesis of a-acyl amino amide derivatives [32]. The scope of this reaction has been explored in solid-phase synthesis and it allows the generation of a large number of compounds with relative ease. This reaction has been employed in the synthesis of a library of C-glycoside conjugated amino amides [33]. Scheme 14.14 shows that, on reaction with carboxylic acids 38, isocyanides 39, and Rink amide resin derivatized with different amino acids 40, the C-fucose aldehyde 37 results in the library synthesis of C-linked fucosyl amino acids 41 as potential mimics of sialyl Lewis. ... 

We anticipate that the current shift in combinatorial chemistry libraries away from numerically large to more focused, target-oriented libraries will continue in the near future and that these hbraries will be helpful in developing ligands with improved binding characteristics. It is also plausible that such a shift may open efficient inhibitor and ligand discovery opportunities to academic laboratories. 

One of the most developed methods used in combinatorial chemistry libraries preparation is solid-phase organic synthesis (SPOS) based on the Merrifield method for peptide synthesis [128]. A great number of such libraries have been prepared on a solid support, generally a functionalized polystyrene resin cross-linked with a small amount of divinylbenzene. Recently, it was demonstrated that micro-wave irradiation can be applied to solid-phase immobilized reagents to reduce significantly the reaction time. Those readers who are interested in such processes we would like to refer to more extensive reviews published by Chamberlin et al. [129] and Kappe [130], while in this chapter we are giving most common examples. 

Virtual chemistry is taken to mean the universe of compounds we could make but haven t. An example would be a combinatorial chemistry library, from which only a subset is synthesised. In principle, any other member of the library is also synthetically accessible. The size of the universe is the product of the numbers of R-groups and can quickly reach infeasibly large numbers. Workers at Pfizer estimate that this accessible universe just within Pfizer is 10 compounds, compared to the < 5 million compounds in the archive. It is impractical to explicitly enumerate all these compounds and to search them, so two methods have been developed to narrow down the search space. Lessel et describe further improvements to the colibri... 

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