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


Unzue, Andrea; Xu, Ming; Dong, Jing; Wiedmer, Lars; Spiliotopoulos, Dimitrios; Caflisch, Amedeo; Nevado, Cristina (2016). Fragment-based design of selective nanomolar ligands of the crebbp bromodomain. Journal of Medicinal Chemistry, 59(4):1350-1356.

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).

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).

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Additional indexing

Item Type:Journal Article, refereed, further contribution
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry

07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:2016
Deposited On:20 Nov 2015 11:19
Last Modified:31 May 2016 18:29
Publisher:American Chemical Society (ACS)
ISSN:0022-2623
Publisher DOI:https://doi.org/10.1021/acs.jmedchem.5b00172
PubMed ID:26043365

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