Compound library design definition

The Reasoner combines evidence from all sources and makes deductions from this evidence. The combination of evidence results in a single "confidence level" for each substructure. These confidence levels designate the degree to which the evidence supports the presence of the substructure in the unknown compound. They range from -100% (substructure definitely absent), through 0% (no information), to +100% (substructure definitely present). The confidence levels are ultimately derived from statistical analysis of representative spectral libraries. Details of the generation and propagation of confidence levels will be described in a separate report.(28)... 

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. 

The design strategies employed to improve combinatorial chemistry have evolved considerably since the early days of peptide and peptidomimetic libraries. The main concern early was on the availability of suitable synthetic methods that could be applied to the synthesis of libraries of small molecules however, this early obstacle has been intensively addressed and at this point can be considered overcome (for examples of new methodology developed for library production see Ref 21). With the ability in hand to prepare many different types of molecules in a variety of formats, the current challenge is to decide what compounds to make. As a consequence, much attention is now focused on the definition and analysis of chemical diversity. 

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