Fragment-Based Design of Selective Nanomolar Ligands of the CREBBP Bromodomain

Novel ligands of the CREBBP bromodomain
were identified by fragment-based
docking. The in silico discovered hits have been optimized by chemical
synthesis into selective nanomolar compounds, thereby preserving the
ligand efficiency. The selectivity for the CREBBP bromodomain over
other human bromodomain subfamilies has achieved by a benzoate moiety
which was predicted by docking to be involved in favorable electrostatic
interactions with the Arg1173 side chain, a prediction that could
be verified a posteriori by the high-resolution crystal structure
of the CREBBP bromodomain in complex with ligand 6 and
also by MD simulations (see Xu, M.; Unzue, A.; Dong, J.; Spiliotopoulos, D.; Nevado, C.; Caflisch, A. Discovery
of CREBBP bromodomain inhibitors by high-throughput docking and hit
optimization guided by molecular dynamics. J. Med. Chem. 2015, DOI: 10.1021/acs.jmedchem.5b00171).