Diversity of compound libraries

Gorse, D., Lahana, R. Functional diversity of compound libraries. Curr. Opin. Chem. Biol. 2000,4, 287—294. 

Centerpieces of combinatorial concepts include the synthesis of compound libraries instead of the preparation of single target compounds. Library synthesis is supplemented by approaches to optimize the diversity of a compound collection (diversity-oriented synthesis) and by efforts to create powerful interfaces between combinatorial synthesis and bioassays. 

Matter, H. Computational approaches towards the quantification of molecular diversity and design of compound libraries. In Modern Methods of Drug Discovery, Hillisch, A. and Hilgenfeld,... 

When molecules are represented by high-dimensional descriptors such as 2D fingerprints or several hundred topological indices, then the diversity of a library of compounds is usually calculated using a function based on the pairwise (dis)similarities of the molecules. Pairwise similarity can be quantified using a similarity or distance coefficient. The Tanimoto coefficient is most often used with binary fingerprints and is given by the formula below ... 

Schreiber and co-workers have shown that this approach is useful in the preparation of compound libraries. One of their examples is a diversity-oriented synthesis of polycyclic scaffolds through the Perrier reaction followed by the PKR of a glycal template on solid support (Equation (35)). 

Our design process calls for ab initio specification of all reaction products for direct use in subsequent molecular selection (diversity) processes. Other approaches base the selection of compounds for synthesis solely on reagent properties. Thus the diversity of the library is based on reagent properties rather than those of the final products. Although this is inherently easier to carry out it can detrimentally... 

The current chemical space is occupied by compounds isolated from nature, synthesised by conventional solution phase synthesis, solid phase combinatorial synthesis and by smaller fragment based libraries. These libraries vary significantly both in their size and complexity. The comparison of diversity of these libraries and their impact as drug leads is reviewed in this chapter. 

Assessing the diversity of various compound classes has been challenging. A number of descriptor-based approaches have been applied to assess the diversity of various libraries and compared with existing drugs. 

The diversity of a library of compounds denotes the degree of heterogeneity, structural range or dissimilarity within the set of compounds. A number of different diversity metrics have been suggested and all are based, either directly or indirectly, on the concept of intermolecular similarity or distance. Determining the (dis)similarity between two molecules requires firstly that the molecules are represented by appropriate structural descriptors and secondly that a quantitative method of determining the degree of resemblance between the two sets of descriptors exists. 

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