Recent trends in library design: 'rational design' revisited

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 dominated the field of lead discovery in the 1990s, with design methods ranging from arbitrary and property-based reagent selection to product-based approaches. Over time, however, there has been a downward trend in library size as the genomics revolution and the increasing availability of target protein structures from X-ray crystallography and homology modeling have increased the volume of information concerning desired targets. Concurrently, computing grids and CPU clusters have facilitated the development of structure-based tools that are able to screen hundreds of thousands of molecules. Smaller, 'smarter' combinatorial and focused parallel libraries have replaced the unfocused large libraries in the drug design paradigm of the 21st century. While diversity continues to play a role in lead discovery, the focus of current library design methods has shifted to scaffold design and bio-isostere searching, with a greatly needed emphasis on synthetic feasibility.