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PDBsum entry 5q0e
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Hydrolase/hydrolase inhibitor
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PDB id
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5q0e
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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 [(4s,8s)-8-({(2e)-3- [5-chloro-2-(1h-tetrazol-1-yl)phenyl]prop-2-enoyl}amino)-4-methyl-2- oxo-1,3,4,5,6,7,8,10-octahydro-2h-12,9-(azeno)-1,10- benzodiazacyclotetradecin-15-yl]carbamate
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Structure:
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Coagulation factor xi. Chain: a. Fragment: heavy chain (unp residues 388-625). Synonym: fxi,plasma thromboplastin antecedent,pta. Engineered: 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: 469008.
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Resolution:
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2.12Å
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R-factor:
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0.174
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R-free:
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0.196
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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).
Macrocyclic inhibitors of Factor XIa: Discovery of alkyl-substituted macrocyclic amide linkers with improved potency.
Bioorg Med Chem Lett,
27,
3833-3839.
PubMed id:
DOI:
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Date:
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01-May-17
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Release date:
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12-Jul-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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Bioorg Med Chem Lett
27:3833-3839
(2017)
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PubMed id:
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Macrocyclic inhibitors of Factor XIa: Discovery of alkyl-substituted macrocyclic amide linkers with improved potency.
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J.R.Corte,
W.Yang,
T.Fang,
Y.Wang,
H.Osuna,
A.Lai,
W.R.Ewing,
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,
M.L.Quan,
R.R.Wexler,
P.Y.S.Lam.
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ABSTRACT
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Optimization of macrocyclic inhibitors of FXIa is described which focused on
modifications to both the macrocyclic linker and the P1 group. Increases in
potency were discovered through interactions with a key hydrophobic region near
the S1 prime pocket by substitution of the macrocyclic linker with small alkyl
groups. Both the position of substitution and the absolute stereochemistry of
the alkyl groups on the macrocyclic linker which led to improved potency varied
depending on the ring size of the macrocycle. Replacement of the
chlorophenyltetrazole cinnamide P1 in these optimized macrocycles reduced the
polar surface area and improved the oral bioavailability for the series, albeit
at the cost of a decrease in potency.
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