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Fluorine in PDB 6w50: Factor Xia in Complex with the Inhibitor Methyl ((10R,14S)- 14-(4-(3- Chloro-2,6-Difluorophenyl)-6-Oxo-3,6-Dihydro- 1(2H)-Pyridinyl)-10- Methyl-9-Oxo-8,16- Diazatricyclo[13.3.1.0~2,7~]Nonadeca-1(19),2,4,6, 15,17- Hexaen-5-Yl)Carbamate

Enzymatic activity of Factor Xia in Complex with the Inhibitor Methyl ((10R,14S)- 14-(4-(3- Chloro-2,6-Difluorophenyl)-6-Oxo-3,6-Dihydro- 1(2H)-Pyridinyl)-10- Methyl-9-Oxo-8,16- Diazatricyclo[13.3.1.0~2,7~]Nonadeca-1(19),2,4,6, 15,17- Hexaen-5-Yl)Carbamate

All present enzymatic activity of Factor Xia in Complex with the Inhibitor Methyl ((10R,14S)- 14-(4-(3- Chloro-2,6-Difluorophenyl)-6-Oxo-3,6-Dihydro- 1(2H)-Pyridinyl)-10- Methyl-9-Oxo-8,16- Diazatricyclo[13.3.1.0~2,7~]Nonadeca-1(19),2,4,6, 15,17- Hexaen-5-Yl)Carbamate:
3.4.21.27;

Protein crystallography data

The structure of Factor Xia in Complex with the Inhibitor Methyl ((10R,14S)- 14-(4-(3- Chloro-2,6-Difluorophenyl)-6-Oxo-3,6-Dihydro- 1(2H)-Pyridinyl)-10- Methyl-9-Oxo-8,16- Diazatricyclo[13.3.1.0~2,7~]Nonadeca-1(19),2,4,6, 15,17- Hexaen-5-Yl)Carbamate, PDB code: 6w50 was solved by S.Sheriff, with X-Ray Crystallography technique. A brief refinement statistics is given in the table below:

Resolution Low / High (Å) 35.54 / 1.95
Space group P 32 2 1
Cell size a, b, c (Å), α, β, γ (°) 78.860, 78.860, 106.620, 90.00, 90.00, 120.00
R / Rfree (%) 15.4 / 17.2

Other elements in 6w50:

The structure of Factor Xia in Complex with the Inhibitor Methyl ((10R,14S)- 14-(4-(3- Chloro-2,6-Difluorophenyl)-6-Oxo-3,6-Dihydro- 1(2H)-Pyridinyl)-10- Methyl-9-Oxo-8,16- Diazatricyclo[13.3.1.0~2,7~]Nonadeca-1(19),2,4,6, 15,17- Hexaen-5-Yl)Carbamate also contains other interesting chemical elements:

Chlorine (Cl) 1 atom

Fluorine Binding Sites:

The binding sites of Fluorine atom in the Factor Xia in Complex with the Inhibitor Methyl ((10R,14S)- 14-(4-(3- Chloro-2,6-Difluorophenyl)-6-Oxo-3,6-Dihydro- 1(2H)-Pyridinyl)-10- Methyl-9-Oxo-8,16- Diazatricyclo[13.3.1.0~2,7~]Nonadeca-1(19),2,4,6, 15,17- Hexaen-5-Yl)Carbamate (pdb code 6w50). This binding sites where shown within 5.0 Angstroms radius around Fluorine atom.
In total 2 binding sites of Fluorine where determined in the Factor Xia in Complex with the Inhibitor Methyl ((10R,14S)- 14-(4-(3- Chloro-2,6-Difluorophenyl)-6-Oxo-3,6-Dihydro- 1(2H)-Pyridinyl)-10- Methyl-9-Oxo-8,16- Diazatricyclo[13.3.1.0~2,7~]Nonadeca-1(19),2,4,6, 15,17- Hexaen-5-Yl)Carbamate, PDB code: 6w50:
Jump to Fluorine binding site number: 1; 2;

Fluorine binding site 1 out of 2 in 6w50

Go back to Fluorine Binding Sites List in 6w50
Fluorine binding site 1 out of 2 in the Factor Xia in Complex with the Inhibitor Methyl ((10R,14S)- 14-(4-(3- Chloro-2,6-Difluorophenyl)-6-Oxo-3,6-Dihydro- 1(2H)-Pyridinyl)-10- Methyl-9-Oxo-8,16- Diazatricyclo[13.3.1.0~2,7~]Nonadeca-1(19),2,4,6, 15,17- Hexaen-5-Yl)Carbamate


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 1 of Factor Xia in Complex with the Inhibitor Methyl ((10R,14S)- 14-(4-(3- Chloro-2,6-Difluorophenyl)-6-Oxo-3,6-Dihydro- 1(2H)-Pyridinyl)-10- Methyl-9-Oxo-8,16- Diazatricyclo[13.3.1.0~2,7~]Nonadeca-1(19),2,4,6, 15,17- Hexaen-5-Yl)Carbamate within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F301

b:41.8
occ:0.75
 F36 A:SWP301 0.0 41.8 0.8
C31 A:SWP301 1.4 37.2 0.8
C32 A:SWP301 2.3 31.9 0.8
C30 A:SWP301 2.4 34.0 0.8
H64 A:SWP301 2.6 31.1 0.8
O A:HOH594 2.7 55.0 1.0
C26 A:SWP301 2.8 34.7 0.8
O A:GLY218 3.2 24.2 1.0
H61 A:SWP301 3.2 38.4 0.8
SG A:CYS219 3.4 22.8 0.5
C27 A:SWP301 3.6 37.9 0.8
C35 A:SWP301 3.6 30.3 0.8
C25 A:SWP301 3.6 34.2 0.8
C33 A:SWP301 3.6 28.0 0.8
H59 A:SWP301 3.8 34.0 0.8
CA A:CYS191 3.9 22.9 0.5
CA A:CYS191 3.9 22.6 0.5
H63 A:SWP301 3.9 36.9 0.8
O A:ALA190 3.9 24.3 1.0
C34 A:SWP301 4.1 29.3 0.8
C A:GLY218 4.1 26.6 1.0
CB A:CYS219 4.2 28.4 0.5
O A:HOH415 4.2 28.3 1.0
C28 A:SWP301 4.3 36.7 0.8
C A:CYS191 4.3 25.4 1.0
H60 A:SWP301 4.5 37.3 0.8
C A:ALA190 4.5 25.1 1.0
CB A:CYS219 4.5 20.1 0.5
H65 A:SWP301 4.5 27.4 0.8
N A:LYS192 4.5 22.4 1.0
N A:CYS191 4.5 22.9 1.0
CA A:CYS219 4.5 25.7 0.5
CA A:CYS219 4.6 21.5 0.5
N A:GLY216 4.6 18.7 1.0
O A:GLY216 4.6 23.0 1.0
F37 A:SWP301 4.7 34.3 0.8
N A:CYS219 4.7 23.1 1.0
SG A:CYS191 4.7 28.3 0.5
C24 A:SWP301 4.7 34.8 0.8
CA A:GLY216 4.9 18.7 1.0
CB A:CYS191 4.9 23.3 0.5
CB A:CYS191 4.9 23.8 0.5
O A:CYS191 4.9 24.1 1.0
SG A:CYS191 4.9 27.7 0.5
C A:GLY216 5.0 23.6 1.0

Fluorine binding site 2 out of 2 in 6w50

Go back to Fluorine Binding Sites List in 6w50
Fluorine binding site 2 out of 2 in the Factor Xia in Complex with the Inhibitor Methyl ((10R,14S)- 14-(4-(3- Chloro-2,6-Difluorophenyl)-6-Oxo-3,6-Dihydro- 1(2H)-Pyridinyl)-10- Methyl-9-Oxo-8,16- Diazatricyclo[13.3.1.0~2,7~]Nonadeca-1(19),2,4,6, 15,17- Hexaen-5-Yl)Carbamate


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 2 of Factor Xia in Complex with the Inhibitor Methyl ((10R,14S)- 14-(4-(3- Chloro-2,6-Difluorophenyl)-6-Oxo-3,6-Dihydro- 1(2H)-Pyridinyl)-10- Methyl-9-Oxo-8,16- Diazatricyclo[13.3.1.0~2,7~]Nonadeca-1(19),2,4,6, 15,17- Hexaen-5-Yl)Carbamate within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F301

b:34.3
occ:0.75
 F37 A:SWP301 0.0 34.3 0.8
C35 A:SWP301 1.3 30.3 0.8
C34 A:SWP301 2.3 29.3 0.8
C30 A:SWP301 2.4 34.0 0.8
C26 A:SWP301 2.8 34.7 0.8
CL1 A:SWP301 2.9 27.4 0.8
C A:SER214 2.9 19.8 1.0
N A:TRP215 2.9 16.9 1.0
CG2 A:THR213 3.0 17.6 1.0
N A:SER214 3.1 17.3 1.0
O A:SER214 3.1 18.5 1.0
H60 A:SWP301 3.1 37.3 0.8
CA A:TRP215 3.4 18.2 1.0
C25 A:SWP301 3.4 34.2 0.8
C27 A:SWP301 3.5 37.9 0.8
CA A:SER214 3.5 17.9 1.0
H59 A:SWP301 3.5 34.0 0.8
C31 A:SWP301 3.6 37.2 0.8
C33 A:SWP301 3.6 28.0 0.8
C A:THR213 3.7 20.2 1.0
H61 A:SWP301 3.9 38.4 0.8
C A:TRP215 3.9 20.8 1.0
OG A:SER195 3.9 16.3 0.5
O A:TRP215 4.1 19.6 1.0
C32 A:SWP301 4.1 31.9 0.8
CB A:THR213 4.2 19.6 1.0
CA A:THR213 4.2 16.2 1.0
O A:THR213 4.3 19.3 1.0
O A:VAL227 4.4 19.0 1.0
C24 A:SWP301 4.4 34.8 0.8
H65 A:SWP301 4.5 27.4 0.8
CB A:SER195 4.5 19.8 0.5
CB A:ALA190 4.6 20.6 1.0
N A:GLY216 4.7 18.7 1.0
F36 A:SWP301 4.7 41.8 0.8
CA A:SER195 4.8 17.1 0.5
CB A:TRP215 4.8 16.8 1.0
CA A:SER195 4.8 17.0 0.5
C28 A:SWP301 4.8 36.7 0.8
CB A:SER214 4.8 20.3 1.0
CB A:SER195 4.9 19.3 0.5

Reference:

W.Yang, Y.Wang, A.Lai, C.G.Clark, J.R.Corte, T.Fang, P.J.Gilligan, Y.Jeon, K.B.Pabbisetty, R.A.Rampulla, A.Mathur, M.Kaspady, P.R.Neithnadka, A.Arumugam, S.Raju, K.A.Rossi, J.E.Myers, S.Sheriff, Z.Lou, J.J.Zheng, S.A.Chacko, J.M.Bozarth, Y.Wu, E.J.Crain, P.C.Wong, D.A.Seiffert, J.M.Luettgen, P.Y.S.Lam, R.R.Wexler, W.R.Ewing. Discovery of A High Affinity, Orally Bioavailable Macrocyclic Fxia Inhibitor with Antithrombotic Activity in Preclinical Species. J.Med.Chem. 2020.
ISSN: ISSN 0022-2623
PubMed: 32456431
DOI: 10.1021/ACS.JMEDCHEM.0C00464
Page generated: Fri Aug 2 03:35:11 2024

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