Product-based design combinatorial optimization

The compound selection methods described thus far can be used to select compounds for screening from an in-house collection, or to select which compounds to purchase from an external supplier. In combinatorial library design, however, it is necessary to select subsets of reactants for actual synthesis. The two main strategies for combinatorial library design are reactant-based selection and product-based selection. In reactant-based selection, optimized subsets of reactants are selected without consideration of the products that will result and any of the compound selection methods already identified can be used. An early example of reactant-based design is that already described by Martin and colleagues which is based on experimental design and where diverse subsets of reactants were selected for the synthesis of peptoid libraries [1]. 

Optimization based on diversity of products is the method of choice, although this is computationally expensive (see Section 9.5.1 for the disadvantages of educt-based design). Normally, library design is not the rate-limiting step in combinatorial synthesis, so that there is no necessity to apply the fastest computational methods. 

The chapter begins with a discussion of similarity and diversity measures and how they can be applied in a virtual screening context. The various computational filters in use are also discussed. The rest of the chapter is concerned with different approaches to combinatorial library design, beginning with reagent-based methods followed by product-based approaches of cherry picking and combinatorial subset selection. Finally, approaches to designing libraries optimized on multiple properties simultaneously are discussed. 

Product-based library design involves a more complex optimization procedure, which we term combinatorial optimization, where the reagent selection is optimized against the properties of the corresponding products. In this scheme, the combinatorial nature of the sublibrary is maintained through combinatorial constraints, while evaluation of diversity, focusing, or other criteria... 

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