化学
溴尿嘧啶
立体化学
部分
生物信息学
组合化学
对接(动物)
配体(生物化学)
生物化学
受体
基因
医学
乙酰化
护理部
作者
Andrea Unzue,Ming Xu,Jing Dong,L. Wiedmer,Christoph Rademacher,Amedeo Caflisch,Cristina Nevado
标识
DOI:10.1021/acs.jmedchem.5b00172
摘要
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).
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