CHAPTER 6: Fragment-Based Lead Discovery Applied to Protein–Protein Interactions

Many disease processes are modulated by the interaction between two proteins. However, the identification of small-molecule inhibitors with appropriate properties for therapeutic inhibition of such interactions remains extremely challenging. The interacting protein surfaces are usually extensive, quite hydrophobic and with relatively few pockets in which inhibitors can bind. Fragment-based methods have recently demonstrated that hit compounds can be identified where conventional methods such as high-throughput screening have failed. It remains a considerable challenge to optimise these hits, but the fragments give a starting point. This chapter summarises recent experience and published work in this area.