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PDBsum entry 4mep
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Transcription/transcription inhibitor
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PDB id
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4mep
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References listed in PDB file
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Key reference
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Title
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Discovery of novel small-Molecule inhibitors of brd4 using structure-Based virtual screening.
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Authors
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L.R.Vidler,
P.Filippakopoulos,
O.Fedorov,
S.Picaud,
S.Martin,
M.Tomsett,
H.Woodward,
N.Brown,
S.Knapp,
S.Hoelder.
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Ref.
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J Med Chem, 2013,
56,
8073-8088.
[DOI no: ]
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PubMed id
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Abstract
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Bromodomains (BRDs) are epigenetic readers that recognize acetylated-lysine
(KAc) on proteins and are implicated in a number of diseases. We describe a
virtual screening approach to identify BRD inhibitors. Key elements of this
approach are the extensive design and use of substructure queries to compile a
set of commercially available compounds featuring novel putative KAc mimetics
and docking this set for final compound selection. We describe the validation of
this approach by applying it to the first BRD of BRD4. The selection and testing
of 143 compounds lead to the discovery of six novel hits, including four
unprecedented KAc mimetics. We solved the crystal structure of four hits,
determined their binding mode, and improved their potency through synthesis and
the purchase of derivatives. This work provides a validated virtual screening
approach that is applicable to other BRDs and describes novel KAc mimetics that
can be further explored to design more potent inhibitors.
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