Rational Hit Generation

In the subsequent section, we will show how the design of focused libraries can be used for the hit generation. Especially, we will present the design of sEH (soluble epoxide hydrolase) targeted libraries [7]. Based on the X-ray binding 

Lead Generation Methods, Stirate es, and Case Studies, First Edition. Edited by Jorg Holenz. 

Rescaffolding, bioisosteric replacement, or fragment replacement all describe workflows where a part of a molecule is replaced by another chemical moiety by retaining the biological activity [13]. The aim of this process is the design of molecules with novel IP or different properties. This concept has a long history in medicinal chemistry, but recently this process is heavily supported by methods of computational chemistry. Based on the retrospective evaluation of COX inhibitors, we will discuss this approach in more detail. 

Besides the presented methods there are a lot of other ways to generate hits in pharmaceutical industry. Methods like SOSA (selective optimization of side activities) [16] and fragment-based approaches are presented in other chapters and are therefore not discussed here. We have tried to provide an overview of the most often used - at least from our viewpoint - lead generation method in this chapter. It is the authors experience that no single lead generation method 

VS may be a suitable strategy, while in the absence of all target-specific information only chemogenomics methods are suitable. Often, a combination or a simultaneous application of several lead generation strategies is applied. 

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