Discovery of Novel BRD4 Ligand Scaffolds by Automated Navigation of the Fragment Chemical Space

摘要

Fragment-based drug discovery (FBDD) is a very effective hit identification method. However, the evolution of fragment hits into suitable leadsremains challenging and largely artisanal. Fragment evolution is often scaffold-centric,meaning that its outcome depends crucially on the chemical structure of the startingfragment. Considering that fragment screening libraries cover only a small proportion ofthe corresponding chemical space, hits should be seen as probes highlighting privilegedareas of the chemical space rather than actual starting points. We have developed anautomated computational pipeline to mine the chemical space around any specificfragment hit, rapidlyfinding analogues that share a common interaction motif but arestructurally novel and diverse. On a prospective application on the bromodomain-containing protein 4 (BRD4), starting from a known fragment, the platform yieldsactive molecules with nonobvious scaffold changes. The procedure is fast andinexpensive and has the potential to uncover many hidden opportunities in FBDD