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

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