Fragment-based covalent ligand discovery

Molecular docking and ligand specificity in fragment-based inhibitor discovery.

Fragment screens have successfully identified new scaffolds in drug discovery, often with relatively high hit rates (5%) using small screening libraries (1,000-10,000 compounds). This raises two questions: would other noteworthy chemotypes be found were one to screen all commercially available fragments (>300,000), and does the success rate imply low specificity of fragments? We used molecular ...

Fragment - based Lead Discovery

Fragment-Based Drug Discovery

Fragment-based drug discovery (FBDD), while still a relatively new approach, has been so successful for identifying ligands for protein targets that it is alreadywidely regarded as representing a sea-change in drug discovery techniques. The strategy involves identifying small (typically ,300Da), low-affinity ligands (‘fragments’) and combining or expanding these to produce larger, higher-affini...

Fragment-based drug discovery applied to Hsp90. Discovery of two lead series with high ligand efficiency.

Inhibitors of the chaperone Hsp90 are potentially useful as chemotherapeutic agents in cancer. This paper describes an application of fragment screening to Hsp90 using a combination of NMR and high throughput X-ray crystallography. The screening identified an aminopyrimidine with affinity in the high micromolar range and subsequent structure-based design allowed its optimization into a low nano...

Tethering: fragment-based drug discovery.

The genomics revolution has provided a deluge of new targets for drug discovery. To facilitate the drug discovery process, many researchers are turning to fragment-based approaches to find lead molecules more efficiently. One such method, Tethering1, allows for the identification of small-molecule fragments that bind to specific regions of a protein target. These fragments can then be elaborate...