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PDBsum entry 1mq5
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Blood clotting
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PDB id
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1mq5
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Crystal structures of two potent nonamidine inhibitors bound to factor xa.
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Authors
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M.Adler,
M.J.Kochanny,
B.Ye,
G.Rumennik,
D.R.Light,
S.Biancalana,
M.Whitlow.
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Ref.
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Biochemistry, 2002,
41,
15514-15523.
[DOI no: ]
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PubMed id
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Abstract
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There has been intense interest in the development of factor Xa inhibitors for
the treatment of thrombotic diseases. Our laboratory has developed a series of
novel non-amidine inhibitors of factor Xa. This paper presents two crystal
structures of compounds from this series bound to factor Xa. The first structure
is derived from the complex formed between factor Xa and compound 1. Compound 1
was the first non-amidine factor Xa inhibitor from our lab that had measurable
potency in an in vitro assay of anticoagulant activity. The second compound, 2,
has a molar affinity for factor Xa (K(iapp)) of 7 pM and good bioavailability.
The two inhibitors bind in an L-shaped conformation with a chloroaromatic ring
buried deeply in the S1 pocket. The opposite end of these compounds contains a
basic substituent that extends into the S4 binding site. A chlorinated phenyl
ring bridges the substituents in the S1 and S4 pockets via amide linkers. The
overall conformation is similar to the previously published structures for
amidine-based inhibitors complexed with factor Xa. However, there are
significant differences in the interactions between the inhibitor and the
protein at the atomic level. Most notably, there is no group that forms a salt
bridge with the carboxylic acid at the base of the S1 pocket (Asp189). Each
inhibitor forms only one well-defined hydrogen bond to the protein. There are no
direct charge-charge interactions. The results indicate that electrostatic
interactions play a secondary role in the binding of these potent inhibitors.
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Secondary reference #1
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Title
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Preparation, Characterization, And the crystal structure of the inhibitor zk-807834 (ci-1031) complexed with factor xa.
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Authors
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M.Adler,
D.D.Davey,
G.B.Phillips,
S.H.Kim,
J.Jancarik,
G.Rumennik,
D.R.Light,
M.Whitlow.
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Ref.
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Biochemistry, 2000,
39,
12534-12542.
[DOI no: ]
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PubMed id
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Secondary reference #2
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Title
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Crystal structures of human factor xa complexed with potent inhibitors.
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Authors
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S.Maignan,
J.P.Guilloteau,
S.Pouzieux,
Y.M.Choi-Sledeski,
M.R.Becker,
S.I.Klein,
W.R.Ewing,
H.W.Pauls,
A.P.Spada,
V.Mikol.
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Ref.
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J Med Chem, 2000,
43,
3226-3232.
[DOI no: ]
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PubMed id
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Secondary reference #3
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Title
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Discovery of n-[2-[5-[Amino(imino)methyl]-2-Hydroxyphenoxy]-3, 5-Difluoro-6-[3-(4, 5-Dihydro-1-Methyl-1h-Imidazol-2-Yl)phenoxy]pyridin-4-Yl]-N-Methylgl y cine (zk-807834): a potent, Selective, And orally active inhibitor of the blood coagulation enzyme factor xa.
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Authors
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G.B.Phillips,
B.O.Buckman,
D.D.Davey,
K.A.Eagen,
W.J.Guilford,
J.Hinchman,
E.Ho,
S.Koovakkat,
A.Liang,
D.R.Light,
R.Mohan,
H.P.Ng,
J.M.Post,
K.J.Shaw,
D.Smith,
B.Subramanyam,
M.E.Sullivan,
L.Trinh,
R.Vergona,
J.Walters,
K.White,
M.Whitlow,
S.Wu,
W.Xu,
M.M.Morrissey.
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Ref.
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J Med Chem, 1998,
41,
3557-3562.
[DOI no: ]
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PubMed id
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