Evaluation of reactant-based and product-based approaches to the design of combinatorial libraries

The large numbers of compounds that are now available in drug discovery programmes have resulted in the need for methods to select compounds, both from external suppliers and in combinatorial library design procedures. In this article we describe a method that has been developed for scoring and ranking compounds according to their likelihood of exhibiting activity. The method can be used to determine the order in which compounds should be screened as well as to guide compound acquisition programmes. We then describe a series of experiments we have conducted that explore the benefits of designing combinatorial libraries through an analysis of product space rather than reactant space. The experiments are based on several different diversity metrics and molecular descriptors. We also show how product-based selection allows multi-objectives to be optimised simultaneously, for example, diversity and physicochemical properties, allowing the design of diverse and drug-like libraries.