Reagent-Based and Product-Based Computational Strategies in Library Design

With the current and ever-growing offering of reagents along with the vast palette of organic reactions, virtual libraries accessible to combinatorial chemists have dramatically increased in size. Yet, extracting suitable subsets for experimentation is an essential step in the design of combinatorial libraries. Several approaches to this problem can be envisaged, involving either reagent-based or product-based considerations. Reagent-based designs tend to be popular with chemists, as they provide highly practical means of weeding extensive reagent lists based on property and substructure considerations. They can also provide suitable reagent selections for model studies. However, reagent-based designs also overlook the extent of chemical transformations involved in generating products. Several studies have demonstrated the superiority of product-based designs in yielding diverse and representative subsets. Although more computationally intensive, product-based approaches present significant advantages, and they are also more amenable to the incorporation of drug-like restraints.