Fragment-based screening
Over the past few years a novel method for designing new leads in drug discovery has been emerging: fragment-based screening. In its simplest incarnation, this method involves soaking small (100-300 Da), drug-like, organic compounds into pre-formed protein crystals. As protein crystals are highly porous, fragments that have an affinity for a protein will bind at its active site, while those that do not will remain in the solvent channels. Binding at the active site is determined using X-ray crystallography to detect difference density in the active site. Using high-throughput crystallographic methods, a large number of fragments can be assessed in a relatively short time; typically 10-100 compounds can be scanned in a day. The method can detect fragments with relatively low affinity, 100 μM-10 mM. The method is well suited to take advantage of the improvements in automation, software and brighter X-ray sources that have become available in recent years.
Solutions
- Fragment-based screening services: ActiveSight
- Macromolecular crystallography systems: Ultimate HomeLab™