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PDBsum entry 4cre
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References listed in PDB file
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Key reference
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Title
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Creating novel activated factor XI inhibitors through fragment based lead generation and structure aided drug design.
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Authors
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O.Fjellström,
S.Akkaya,
H.G.Beisel,
P.O.Eriksson,
K.Erixon,
D.Gustafsson,
U.Jurva,
D.Kang,
D.Karis,
W.Knecht,
V.Nerme,
I.Nilsson,
T.Olsson,
A.Redzic,
R.Roth,
J.Sandmark,
A.Tigerström,
L.Öster.
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Ref.
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Plos One, 2015,
10,
e0113705.
[DOI no: ]
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PubMed id
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Abstract
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Activated factor XI (FXIa) inhibitors are anticipated to combine anticoagulant
and profibrinolytic effects with a low bleeding risk. This motivated a structure
aided fragment based lead generation campaign to create novel FXIa inhibitor
leads. A virtual screen, based on docking experiments, was performed to generate
a FXIa targeted fragment library for an NMR screen that resulted in the
identification of fragments binding in the FXIa S1 binding pocket. The neutral
6-chloro-3,4-dihydro-1H-quinolin-2-one and the weakly basic quinolin-2-amine
structures are novel FXIa P1 fragments. The expansion of these fragments towards
the FXIa prime side binding sites was aided by solving the X-ray structures of
reported FXIa inhibitors that we found to bind in the S1-S1'-S2' FXIa binding
pockets. Combining the X-ray structure information from the identified S1
binding 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment and the S1-S1'-S2'
binding reference compounds enabled structure guided linking and expansion work
to achieve one of the most potent and selective FXIa inhibitors reported to
date, compound 13, with a FXIa IC50 of 1.0 nM. The hydrophilicity and large
polar surface area of the potent S1-S1'-S2' binding FXIa inhibitors compromised
permeability. Initial work to expand the 6-chloro-3,4-dihydro-1H-quinolin-2-one
fragment towards the prime side to yield molecules with less hydrophilicity
shows promise to afford potent, selective and orally bioavailable compounds.
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