How to avoid rediscovering the known

For anyone who has participated in a screening exercise in a pharmaceutical or biotech setting with the aim to discover hits against protein targets, it is evident that a single screening exercise does not always offer hits of sufficient quality to be progressed into a lead compound. Often, more than one screen is needed. The premise in conducting a new screening exercise is to find "better" hits that are chemically and pharmacologically more attractive. As we move into challenging, new target classes, the need of new methods to find tractable hits is ever more urgent and the availability of differentiated backup compounds is crucial to sustain a clinical program. The obvious alternate routes to conduct the new screen include an improved compound library, a larger compound library, and different or more sensitive detection methods. As many of us have experienced firsthand, repeating a screen without drastically changing the chemical nature of the compound library or information content of the readout likely will offer only variations of the original hits. This chapter describes the strategies to adopt in fragment-based lead discovery to avoid rediscovering the known.