The “Gatekeeper” Residue Influences the Mode of Binding of Acetyl Indoles to Bromodomains

Small-molecule
hits for the bromodomains of CREBBP and BAZ2B have
been identified by scaffold hopping followed by docking of a set of
∼200 compounds containing the acetyl indole scaffold. Chemical
synthesis of nearly 30 derivatives has resulted in ligands of representatives
of three subfamilies of human bromodomains with favorable ligand efficiency.
The X-ray crystal structures of three different bromodomains (CREBBP,
BAZ2B, and BRPF1b) in complex with acetyl indole derivatives reveal
the influence of the gatekeeper residue on the orientation of small-molecule
ligands in the acetyl lysine binding site.