title: Fragment-Based Design of Selective Nanomolar Ligands of the CREBBP Bromodomain.
abstract: 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).
authors.affiliation: Department of of Chemistry, University of Zürich , Winterthurerstrasse 190, CH-8057, Zürich, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Unzue
authors.affiliation: Department of of Biochemistry, University of Zürich , Winterthurerstrasse 190, CH-8057, Zürich, Switzerland.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of of Biochemistry, University of Zürich , Winterthurerstrasse 190, CH-8057, Zürich, Switzerland.
authors.forename: Jing
authors.initials: J
authors.lastname: Dong
authors.affiliation: Department of of Biochemistry, University of Zürich , Winterthurerstrasse 190, CH-8057, Zürich, Switzerland.
authors.forename: Lars
authors.initials: L
authors.lastname: Wiedmer
authors.affiliation: Department of of Biochemistry, University of Zürich , Winterthurerstrasse 190, CH-8057, Zürich, Switzerland.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Spiliotopoulos
authors.affiliation: Department of of Biochemistry, University of Zürich , Winterthurerstrasse 190, CH-8057, Zürich, Switzerland.
authors.forename: Amedeo
authors.initials: A
authors.lastname: Caflisch
authors.affiliation: Department of of Chemistry, University of Zürich , Winterthurerstrasse 190, CH-8057, Zürich, Switzerland.
authors.forename: Cristina
authors.initials: C
authors.lastname: Nevado
mesh_terms: D001565:Benzoates / Q000737:chemistry* / Q000494:pharmacology; D050882:CREB-Binding Protein / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D001565:Benzoates; D008024:Ligands; D054852:Small Molecule Libraries; D050882:CREB-Binding Protein; C494363:CREBBP protein, human