Screening against biochemical targets with compact chemical fragments has developed a reputation as a successful early‐stage drug discovery approach, thanks to recent drug approvals. Having weak initial target affinities, fragments require the use of sensitive biophysical technologies (NMR, SPR, thermal shift, ITC, and X‐ray crystallography) to accommodate the practical limits of going smaller. Application of optimized fragment biophysical screening approaches now routinely allows for the rapid identification of fragments with high binding efficiencies. The aim of this chapter is to provide an introduction to fragment library selection and to discuss the suitability of screening approaches adapted for lower‐throughput biophysical techniques. A general description of metrics that are being used in the progression of fragment hits, the need for orthogonal assay testing, and guidance on potential pitfalls are included to assist scientists, considering initiating their own fragment discovery program.
Part of the book: Special Topics in Drug Discovery