Designing Combinatorial Libraries

This section summarizes strategy and practical considerations for designing and analyzing diverse chemical structures in combinatorial or parallel synthesis library format based on concepts and results introduced above. 

Another point is to evaluate which of many library proposals is more diverse and/or better suited for a particular screening application. Here, validated quantitative measures of diversity are routinely applied to assess diversity, representativity plus complementarity to any corporate compound collection. It must be decided whether it is more effective to manufacture a sublibrary variation of an existing library, or to establish a new synthesis scheme with a novel scaffold. 

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RD Brown, YC Martin. Designing combinatorial library mixtures using a genetic algorithm. I Med Chem 40(15) 2304-2313, 1997. 

Gillet VJ. Designing combinatorial libraries optimized on multiple objectives. Methods Mol Biol 2004 275 335-54. 

Once the initial diversity fetish had run its course and management realized that it was inefficient to attempt to span the entirety of chemical space in search of drugs, more rational approaches based on chemoinformatics were developed to design combinatorial libraries and select candidates for screening on the basis of properties that have proven to be associated with successful therapeutics in the past. 

Designing Combinatorial Libraries Optimized on Multiple Objectives... 

Xu G, Wang W, Groves JT, Hecht MH. Self-assembled monolayers from a designed combinatorial library of de novo beta-sheet proteins. Proc Natl Acad Sci USA 2001 98 3652-3657. 

Gillet, V. J. (2004) Designing combinatorial libraries optimized on multiple objectives in methods in molecular biology, in (Bajorath, J., ed.) Chemoinformatics Concepts, Methods, and Tools for Drug Discovery. Humana Press, Totowa, NJ, 275, pp. 335-354. 

CombiDock Tweaks the DOCK algorithm to identify suitable scaffold orientations in the binding pocket. Proceeds using the seed and grow approach to design combinatorial libraries (73)... 

Brown, R.D. and Martin, Y.C. Designing Combinatorial Library Mixtures Using a Genetic Algorithm.. J. Med. Chem., 1997,40,2304-2313. 

DESIGNING COMBINATORIAL LIBRARIES WITH OPTIMAL ADME PROPERTIES... 

Fig. 16 Comparison between random and designed combinatorial libraries of different sizes, a) Random choice of bulding blocks, b) Diverse selection of building blocks, c) Bulding block selection based on diversity of the products. A higher number of different matched compartments marks higher diversity of the library. The library set-up for this example is described in more detail in Section 9.7.

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