Chapter 28 Fragment-Based Lead Discovery

Publisher Summary Fragment-based lead discovery (FBLD) is establishing itself as an approach that holds the promise of delivering leads with greater efficiency and speed when compared to high throughput screening (HTS). In FBLD, small libraries of low molecular weight compounds (typically 120–250 Da) are screened using sensitive biophysical techniques to detect weak binding. Lower absolute affinity of fragments is expected compared to much higher molecular weight hits detected by HTS due to their reduced size and complexity. Through the use of structural biology, it is often then relatively straightforward to optimize these hits to promising lead molecules. There have been a number of recent reviews on fragment-based methods of which two reviews are important that were published in 2004. The reviews aimed at medicinal chemists and gave comprehensive lists of examples of how lead molecules have been derived starting from fragments. This chapter focuses on examples that have been published since these two reviews and, where the starting fragment is less than 300 Da and has an affinity against the target of 425 mM. The latter criterion means that it would have been difficult to identify the hits using conventional screening methods. The chapter provides an overview of binding mode of the fragments underlining the view that efficient optimization of fragments requires a structure-based approach. The chapter briefly outlines the identification of fragments where the optimization is either not described, or only a limited amount of optimization was achieved. Examples are given where lead molecules were successfully derived from fragments.