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PDBsum entry 2bmg
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References listed in PDB file
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Key reference
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Title
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Structural requirements for factor xa inhibition by 3-Oxybenzamides with neutral p1 substituents: combining x-Ray crystallography, 3d-Qsar, And tailored scoring functions.
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Authors
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H.Matter,
D.W.Will,
M.Nazaré,
H.Schreuder,
V.Laux,
V.Wehner.
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Ref.
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J Med Chem, 2005,
48,
3290-3312.
[DOI no: ]
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PubMed id
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Note In the PDB file this reference is
annotated as "TO BE PUBLISHED".
The citation details given above were identified by an automated
search of PubMed on title and author
names, giving a
percentage match of
96%.
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Abstract
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The design, synthesis, and structure-activity relationship of 3-oxybenzamides as
potent inhibitors of the coagulation protease factor Xa are described on the
basis of X-ray structures, privileged structure motifs, and SAR information. A
total of six X-ray structures of fXa/inhibitor complexes led us to identify the
major protein-ligand interactions. The binding mode is characterized by a
lipophilic dichlorophenyl substituent interacting with Tyr228 in the protease S1
pocket, while polar parts are accommodated in S4. This alignment in combination
with docking allowed derivation of 3D-QSAR models and tailored scoring functions
to rationalize biological affinity and provide guidelines for optimization. The
resulting models showed good correlation coefficients and predictions of
external test sets. Furthermore, they correspond to binding site topologies in
terms of steric, electrostatic, and hydrophobic complementarity. Two approaches
to derive tailored scoring functions combining binding site and ligand
information led to predictive models with acceptable predictions of the external
set. Good correlations to experimental affinities were obtained for both AFMoC
(adaptation of fields for molecular comparison) and the novel TScore function.
The SAR information from 3D-QSAR and tailored scoring functions agrees with all
experimental data and provides guidelines and reasonable activity estimations
for novel fXa inhibitors.
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