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PDBsum entry 1v3x
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References listed in PDB file
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Key reference
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Title
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Synthesis and conformational analysis of a non-Amidine factor xa inhibitor that incorporates 5-Methyl-4,5,6,7-Tetrahydrothiazolo[5,4-C]pyridine as s4 binding element.
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Authors
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N.Haginoya,
S.Kobayashi,
S.Komoriya,
T.Yoshino,
M.Suzuki,
T.Shimada,
K.Watanabe,
Y.Hirokawa,
T.Furugori,
T.Nagahara.
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Ref.
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J Med Chem, 2004,
47,
5167-5182.
[DOI no: ]
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PubMed id
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Abstract
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Our exploratory study was based on the concept that a non-amidine factor Xa
(fXa) inhibitor is suitable for an orally available anticoagulant. We
synthesized and evaluated a series of
N-(6-chloronaphthalen-2-yl)sulfonylpiperazine derivatives incorporating various
fused-bicyclic rings containing an aliphatic amine expected to be S4 binding
element. Among this series, 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine
type 61 displayed orally potent anti-fXa activity and evident prolongation of
prothrombin time (PT) with the moderate bioavailability in rats. The X-ray
crystal analysis afforded an obvious binding mode that
5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine and 6-chloronaphthalene
respectively bound to S4 and S1 subsites. In this X-ray study, we discovered a
novel intramolecular S-O close contact. Ab initio energy calculations of model
compounds deduced that conformers with the most close S-O proximity were most
stable. The Mulliken population analysis proposed that this energy profile was
caused by both of electrostatic S-O affinity and N-O repulsion. The results of
these calculations and X-ray analysis suggested a possibility that the
restricted conformation effected the affinity to S4 subsite of fXa.
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Secondary reference #1
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Title
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Structural basis for chemical inhibition of human blood coagulation factor xa.
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Authors
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K.Kamata,
H.Kawamoto,
T.Honma,
T.Iwama,
S.H.Kim.
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Ref.
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Proc Natl Acad Sci U S A, 1998,
95,
6630-6635.
[DOI no: ]
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PubMed id
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Figure 1.
Fig. 1. Chemical formulae of the FX-2212a inhibitor
(2S)-(3'-amidino-3-biphenylyl)-5-(4-pyridylamino)pentanoic acid
and the DX9065a
(2S)-{4-[1-acetimidoyl-(3S)-pyrrolidinyl]oxyphenyl}-3-(7-amidino-2-naphthyl)propionic
acid. Schematic drawing of the interactions between two
inhibitors, DX9065a and FX-2212a, and factor Xa. Hydrogen bonds
are shown as thin dashed lines, and hydrophobic interactions are
shown as thick dashed lines. In the case of Q192, the aliphatic
chain portion of Q192 makes the hydrophobic interaction. The
symbol "  " indicates
that the two interacting aromatic groups are not stacked but are
perpendicular to each other.
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Figure 5.
Fig. 5. (a) Stereo view of the electron density for
FX-2212a in difference electron density maps (contoured at 1.6
 )
calculated after modeling the first EGF domain and the simulated
annealing refinement. The final structure is superimposed. (b)
Binding interactions of FX-2212a (magenta ball and stick) with
Des[1-44] factor Xa in the form 1 crystal. The C  backbone is
shown in blue, and residues involved in interaction are shown as
a yellow ball-and-stick model. Conserved hydrogen bonds in the
three crystallographically independent molecules are shown in
green and a unique hydrogen bond in this interaction is shown in
orange.
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Secondary reference #2
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Title
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X-Ray structure of active site-Inhibited clotting factor xa. Implications for drug design and substrate recognition.
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Authors
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H.Brandstetter,
A.Kühne,
W.Bode,
R.Huber,
W.Von der saal,
K.Wirthensohn,
R.A.Engh.
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Ref.
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J Biol Chem, 1996,
271,
29988-29992.
[DOI no: ]
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PubMed id
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Figure 1.
Fig. 1. Chemical formula of the DX-9065a inhibitor:
(2S)-{4-[1-acetimidoyl-(3S)-pyrrolidinyl]-oxyphenyl}-3-(7-amidino-2-naphthyl)propionic^
acid hydrochloride pentahydrate.
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Figure 3.
Fig. 3. Binding interactions of DX-9065a with fXa. The C^
 plot
and side chains involved in inhibitor binding of DX-9065a-bound^
fXa (yellow) are superimposed with the corresponding atoms of^
arginine-bound fXa (turquoise). The ligand-induced structural
changes at the S1-binding site may be seen at the side chain of^
Asp-189 and along the main chain at Gln-192. The hydrophobic
sleeve^ at the aryl-binding site (S4) is also apparent, with the
cation hole formed by Glu-97 and the carbonyl oxygens of Glu-97
and Lys-96^ at the back.
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The above figures are
reproduced from the cited reference
with permission from the ASBMB
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Secondary reference #3
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Title
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Structure of human des(1-45) factor xa at 2.2 a resolution.
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Authors
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K.Padmanabhan,
K.P.Padmanabhan,
A.Tulinsky,
C.H.Park,
W.Bode,
R.Huber,
D.T.Blankenship,
A.D.Cardin,
W.Kisiel.
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Ref.
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J Mol Biol, 1993,
232,
947-966.
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PubMed id
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