Halogen-enriched fragment libraries as chemical probes for harnessing halogen bonding in fragment-based lead discovery.

Halogen bondinghas recently experienced a renaissance, gaining increased recognition as a useful molecular interaction in the life sciences. Halogen bondsare favorable, fairly directional interactions between an electropositive region on the halogen(the σ-hole) and a number of different nucleophilic interaction partners. Some aspects of halogen bondingare not yet understood well enough to take full advantage of its potential in drug discovery. We describe and present the concept of halogen-enriched fragment libraries. These libraries consist of unique chemical probes, facilitating the identification of favorable halogen bondsby sharing the advantages of classical fragment-based screening. Besides providing insights into the nature and applicability of halogen bonding, halogen-enriched fragment libraries provide smart starting points for hit-to- leadevolution.