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PDBsum entry 5tkt
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Hydrolase/hydrolase inhibitor
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PDB id
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5tkt
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PDB id:
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| Name: |
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Hydrolase/hydrolase inhibitor
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Title:
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Factor xia in complex with the inhibitor methyl ((12e,15s)-15-(((2e)- 3-(5-chloro-2-(1h-tetrazol-1-yl)phenyl)-2-propenoyl)amino)-9-oxo-8, 17,19-triazatricyclo[14.2.1.0~2,7~]nonadeca-1(18),2,4,6,12,16(19)- hexaen-5-yl)carbamate
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Structure:
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Factor xia (light chain). Chain: a. Synonym: fxi,plasma thromboplastin antecedent,pta. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: f11. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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2.12Å
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R-factor:
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0.168
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R-free:
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0.189
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Authors:
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S.Sheriff
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Key ref:
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J.R.Corte
et al.
(2017).
Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker.
J Med Chem,
60,
1060-1075.
PubMed id:
DOI:
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Date:
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07-Oct-16
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Release date:
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01-Mar-17
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PROCHECK
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Headers
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References
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P03951
(FA11_HUMAN) -
Coagulation factor XI from Homo sapiens
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Seq:
Struc:
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625 a.a.
238 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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*
PDB and UniProt seqs differ
at 2 residue positions (black
crosses)
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Enzyme class:
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E.C.3.4.21.27
- coagulation factor XIa.
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Reaction:
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Selective cleavage of Arg-|-Ala and Arg-|-Val bonds in factor IX to form factor IXa.
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DOI no:
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J Med Chem
60:1060-1075
(2017)
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PubMed id:
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Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker.
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J.R.Corte,
T.Fang,
H.Osuna,
D.J.Pinto,
K.A.Rossi,
J.E.Myers,
S.Sheriff,
Z.Lou,
J.J.Zheng,
T.W.Harper,
J.M.Bozarth,
Y.Wu,
J.M.Luettgen,
D.A.Seiffert,
C.P.Decicco,
R.R.Wexler,
M.L.Quan.
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ABSTRACT
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A novel series of macrocyclic FXIa inhibitors was designed based on our lead
acyclic phenyl imidazole chemotype. Our initial macrocycles, which were
double-digit nanomolar FXIa inhibitors, were further optimized with assistance
from utilization of structure-based drug design and ligand bound X-ray crystal
structures. This effort resulted in the discovery of a macrocyclic amide linker
which was found to form a key hydrogen bond with the carbonyl of Leu41 in the
FXIa active site, resulting in potent FXIa inhibitors. The macrocyclic FXIa
series, exemplified by compound 16, had a FXIa Ki = 0.16 nM with potent
anticoagulant activity in an in vitro clotting assay (aPTT EC1.5x = 0.27 μM)
and excellent selectivity against the relevant blood coagulation enzymes.
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Links
