A decade of fragment-based drug design: strategic advances and lessons learned

Abstract

Fragment-based drug design is based on screening smaller numbers of compounds (typically several thousand) in the hopes of finding low-affinity fragments (K_d values in the high micromolar to millimolar range), in contrast to conventional high-throughput screening (HTS), which attempts to evaluate as many compounds as technologically possible (typically a million or more) in the hopes of finding relatively potent drug leads (K_d values ideally less than 1 μM). The combination of broader sampling of the potential chemical universe than HTS and increased hit rates for molecules of low complexity makes fragment-based screening a powerful tool for lead generation. Fragment-based screening is also less prone to artefacts as the low-molecular-mass compounds tend to be more soluble and the methods of detection are simpler and more robust. Two-dimensional, isotope-edited nuclear magnetic resonance (NMR) spectroscopy was the first approach used in fragment-based drug design. It is well suited to this purpose as NMR chemical shifts are exquisitely sensitive to ligand binding, and problems with compound interference can be solved by spectral editing. During the past decade, the popularity of fragment-based screening has grown at a remarkable rate in both industry and academia. A range of different strategies have been developed, including alternative NMR-based approaches that obviate the need for isotope labelling, approaches based on X-ray-crystallography and fragment tethering, which are discussed here. The ability to obtain NMR or X-ray crystal structures on fragment leads has a dramatic influence on the success of fragment-based drug design. The successful applications of fragment-based drug design have provided ample support that the use of fragments could, in many cases, be the most direct route to the best achievable balance between potency and pharmacokinetics.