Structure-based generation of viable leads from small combinatorial libraries.

Parallel synthesis and structure-aided design have begun to converge in the process of drug discovery. Virtual screening using X-ray crystal structures of therapeutic targets to front-load a high-throughput screen or to establish a tractable collection for lower throughput assays has become a standard practice in many lead generation settings. The application of similar techniques for increasing the likelihood of including active compounds in a focused combinatorial library is a natural progression that is beginning to be recognized. In this review, we will cover recent reports of small, focused libraries designed for specific therapeutic targets, and for which X-ray crystallographic data is available.