Library Design: Ligand and Structure-Based Principles for Parallel and Combinatorial Libraries

Abstract

Diversity has historically played a critical role in the design of combinatorial libraries, screening sets, and corporate collections for lead discovery. Large library design in the 1990s ranged from arbitrary through property-based reagent selection to product-based approaches. Over time, however, there has been a downward trend in library size as information about the desired targets increased due to the genomics revolution and the increasing availability of target protein structures from crystallography and homology modeling. Concurrently, computing grids and central processing unit (CPU) clusters have facilitated the development of structure-based tools that screen hundreds of thousands of molecules. Smaller ‘smarter’ combinatorial and focused parallel libraries have replaced those unfocused large libraries in the twenty-first-century drug design paradigm. While diversity-derived libraries still play a role in lead discovery, expectations for their success in other areas of drug discovery were generally unrealized and contributed to the current dominance of target family and target-specific approaches in library design. This chapter reviews methods for both combinatorial and array-based library design with an emphasis on the design of the various types of focused libraries.