TY - JOUR KW - Drug Design KW - fragment-based docking KW - bromodomains KW - selective inhibitors AU - A. Unzue AU - M. Xu AU - J. Dong AU - L. Wiedmer AU - D. Spiliotopoulos AU - A. Caflisch AU - C. Nevado AB -

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).

BT - Journal of Medicinal Chemistry C1 - 0206 DA - 2015 Jul 15 DO - 10.1021/acs.jmedchem.5b00172 IS - 4 J2 - J. Med. Chem. LA - eng M3 - Research Article N2 -

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).

PY - 2016 SE - 1350 SP - 1350 EP - 1356 T2 - Journal of Medicinal Chemistry TI - Fragment-based design of selective nanomolar ligands of the CREBBP bromodomain VL - 59 SN - 1520-4804 ER -