Recent developments in focused library design: targeting gene-families.

For many years, the most frequently optimized qualities of a screening library, or corporate compound collection, were size and diversity. Maximizing the number of diverse hits is the fundamental goal of such strategies. The ostensible justification that "bigger is better" is based on the large, estimated size of small-molecule space and the hypothesis that the notoriously low hit rates from high-throughput screening (HTS) could be overcome by brute force: i.e. by screening more compounds. Published, detailed studies about the success (or failure) of the brute-force strategy are rare, but it is well-known that it did not fulfill expectations. As a result, published reports in recent years have increasingly described methods for designing, selecting or synthesizing gene family-focused or -biased libraries. Moreover, many of the larger compound suppliers now sell such libraries, reflecting the growing interest in them from both the pharmaceutical and biotechnology markets. The trend towards gene family-focused libraries marks the emergence of a different hypothesis about how to increase HTS hit rates and also reflects an increasingly pragmatic focus on the management of screening libraries. An important, underlying assumption in this trend is that a high-quality, general-purpose screening library of manageable size is neither realizable nor desirable. Whether a biasing strategy based on a specific gene family will do a better job of meeting both the scientific and business needs of the drug discovery enterprise still remains to be seen, but it is certainly an active area of current research. This review focuses on the "who, what, why, when, and how" of the design of gene family-focused libraries. Particular attention is given to reports that discuss not only the techniques used, but also any results obtained.