Synthetically efficient combinatorial library

A short overview of synthetic strategies that are currently used in combinatorial chemistry is important to get a better understanding of how to characterize a combinatorial library in the most efficient way. Figure 10.3 presents different strategies for synthesis of combinatorial libraries on an example of a library with three points of randomization (X, Y, Z), three building blocks in each randomization (XI, X2, X3, Yl, Y2, etc., correspondingly), and total complexity of 27 compounds. 

In product-based selection, the properties of the resulting product molecules are taken into account when selecting the reactants. Typically this is done by enumerating the entire virtual library that could potentially be made. Any of the subset selection methods described previously could be used to select a diverse subset of products, however the resulting subset is very unlikely to represent a combinatorial subset. This process is known as cherry-picking and is synthetically inefficient as far as combinatorial synthesis is concerned. Synthetic efficiency is maximized by taking the combinatorial... 

The creation of drug-like molecules capable of CNS penetration from these starting points would be a challenging task. This will be made harder as room for maneuver is limited by the likely demands for isoform selectivity. For a comprehensive review of delivery of peptide and protein drugs across the blood-brain barrier, see [65]. Notably, Ghadiri and co-workers exploited this structural class and have developed an efficient synthetic access to one-bead-one-compound combinatorial libraries of cyclic tetrapeptide analogs with promising subtype selectivity [66, 67]. 

Molecular diversity Synthetic and virtual molecule libraries used in combinatorial chemistry and high throughput screening can only be efficient if they contain as much information as possible. The molecular diversity should be comparable to the diversity of natural compounds. The first combinatorial libraries were biased during screening toward large, hydrophobic molecules, which led to poor bioavailability and the rule-of-5. 

In an effort to compare descriptor distributions between compounds from different sources and synthetic paradigms, Feher and Schmidt [121] used PCA-based methods to compare property distributions from natural products, drugs, and combinatorial libraries. In this case, the authors used chemical space as a common framework to ask questions about the how the origins of compounds are manifest in their structural features at a global level. In particular, this study demonstrates the general dominance of synthetic efficiency, rather than structural diversity, in the preparation of compounds by combinatorial chemistry. The descriptors most able to distinguish natural products from those synthetic molecules studied were those that rendered the latter class easier to make, such as fewer... 

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