1 Introduction to Fragment - based Drug Discovery

Fragment screening is the process of identifying relatively simple, often weakly potent, bioactivemolecules. It is gainingwide acceptance as a successful hit-finding technique both in its own right and as a method of finding hit molecules when traditional high-throughput screening (HTS) methods fail. Fragment hits are typically highly ‘ligand efficient’, i.e. possess a high binding affinity per heavy atom, and thus are ideal for optimisation into clinical candidates with good drug-like properties. Fragment screening is being increasingly proven as a successful means of generating novel chemical starting material for drug discovery programmes. It has been the subject of numerous publications and reviews in the last few years.[1 5] Fragment screening was initially developed to generate hit compounds against targets for which other methods, such as HTS, had been unsuccessful.[6] At the same time, many shortcomings of HTS were becoming increasingly apparent: