Fragment-based design of selective nanomolar ligands of the crebbp bromodomain

Abstract

Novel ligands of the CREBBP bromodomain have been 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 sub-families was 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 back to back paper).