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Fluorine in PDB 5ygx: Structure of BACE1 in Complex with N-(3-((4R,5R,6S)-2-Amino-6-(1,1- Difluoroethyl)-5-Fluoro-4-Methyl-5,6-Dihydro-4H-1,3-Oxazin-4-Yl)-4- Fluorophenyl)-5-(Fluoromethoxy)Pyrazine-2-Carboxamide

Enzymatic activity of Structure of BACE1 in Complex with N-(3-((4R,5R,6S)-2-Amino-6-(1,1- Difluoroethyl)-5-Fluoro-4-Methyl-5,6-Dihydro-4H-1,3-Oxazin-4-Yl)-4- Fluorophenyl)-5-(Fluoromethoxy)Pyrazine-2-Carboxamide

All present enzymatic activity of Structure of BACE1 in Complex with N-(3-((4R,5R,6S)-2-Amino-6-(1,1- Difluoroethyl)-5-Fluoro-4-Methyl-5,6-Dihydro-4H-1,3-Oxazin-4-Yl)-4- Fluorophenyl)-5-(Fluoromethoxy)Pyrazine-2-Carboxamide:
3.4.23.46;

Protein crystallography data

The structure of Structure of BACE1 in Complex with N-(3-((4R,5R,6S)-2-Amino-6-(1,1- Difluoroethyl)-5-Fluoro-4-Methyl-5,6-Dihydro-4H-1,3-Oxazin-4-Yl)-4- Fluorophenyl)-5-(Fluoromethoxy)Pyrazine-2-Carboxamide, PDB code: 5ygx was solved by K.Nakahara, K.Fuchino, K.Komano, N.Asada, G.Tadano, T.Hasegawa, T.Yamamoto, Y.Sako, M.Ogawa, C.Unemura, M.Hosono, G.Sakaguchi, S.Ando, S.Ohnishi, Y.Kido, T.Fukushima, D.Dhuyvetter, H.Borghys, H.Gijsen, Y.Yamano, Y.Iso, K.Kusakabe, with X-Ray Crystallography technique. A brief refinement statistics is given in the table below:

Resolution Low / High (Å) 20.00 / 2.20
Space group P 61 2 2
Cell size a, b, c (Å), α, β, γ (°) 101.550, 101.550, 170.811, 90.00, 90.00, 120.00
R / Rfree (%) 17.8 / 20.7

Other elements in 5ygx:

The structure of Structure of BACE1 in Complex with N-(3-((4R,5R,6S)-2-Amino-6-(1,1- Difluoroethyl)-5-Fluoro-4-Methyl-5,6-Dihydro-4H-1,3-Oxazin-4-Yl)-4- Fluorophenyl)-5-(Fluoromethoxy)Pyrazine-2-Carboxamide also contains other interesting chemical elements:

Iodine (I) 2 atoms

Fluorine Binding Sites:

The binding sites of Fluorine atom in the Structure of BACE1 in Complex with N-(3-((4R,5R,6S)-2-Amino-6-(1,1- Difluoroethyl)-5-Fluoro-4-Methyl-5,6-Dihydro-4H-1,3-Oxazin-4-Yl)-4- Fluorophenyl)-5-(Fluoromethoxy)Pyrazine-2-Carboxamide (pdb code 5ygx). This binding sites where shown within 5.0 Angstroms radius around Fluorine atom.
In total 5 binding sites of Fluorine where determined in the Structure of BACE1 in Complex with N-(3-((4R,5R,6S)-2-Amino-6-(1,1- Difluoroethyl)-5-Fluoro-4-Methyl-5,6-Dihydro-4H-1,3-Oxazin-4-Yl)-4- Fluorophenyl)-5-(Fluoromethoxy)Pyrazine-2-Carboxamide, PDB code: 5ygx:
Jump to Fluorine binding site number: 1; 2; 3; 4; 5;

Fluorine binding site 1 out of 5 in 5ygx

Go back to Fluorine Binding Sites List in 5ygx
Fluorine binding site 1 out of 5 in the Structure of BACE1 in Complex with N-(3-((4R,5R,6S)-2-Amino-6-(1,1- Difluoroethyl)-5-Fluoro-4-Methyl-5,6-Dihydro-4H-1,3-Oxazin-4-Yl)-4- Fluorophenyl)-5-(Fluoromethoxy)Pyrazine-2-Carboxamide


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 1 of Structure of BACE1 in Complex with N-(3-((4R,5R,6S)-2-Amino-6-(1,1- Difluoroethyl)-5-Fluoro-4-Methyl-5,6-Dihydro-4H-1,3-Oxazin-4-Yl)-4- Fluorophenyl)-5-(Fluoromethoxy)Pyrazine-2-Carboxamide within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F509

b:25.6
occ:1.00
 F4 A:0B5509 0.0 25.6 1.0
C18 A:0B5509 1.3 25.2 1.0
C17 A:0B5509 2.3 24.4 1.0
C7 A:0B5509 2.5 25.0 1.0
C1 A:0B5509 3.0 25.4 1.0
C A:0B5509 3.0 24.0 1.0
CE1 A:PHE108 3.2 23.9 1.0
C2 A:0B5509 3.2 26.0 1.0
CD1 A:PHE108 3.3 24.6 1.0
CE2 A:TYR71 3.4 43.7 1.0
CZ A:TYR71 3.5 42.7 1.0
C16 A:0B5509 3.6 24.7 1.0
C8 A:0B5509 3.7 24.4 1.0
OH A:TYR71 3.7 48.5 1.0
O A:HOH802 3.8 48.1 1.0
CD2 A:TYR71 4.0 43.5 1.0
CD1 A:ILE118 4.0 25.5 1.0
CE1 A:TYR71 4.1 43.2 1.0
F A:0B5509 4.1 27.6 1.0
C9 A:0B5509 4.1 25.4 1.0
C3 A:0B5509 4.2 27.1 1.0
N1 A:0B5509 4.5 23.9 1.0
CZ A:PHE108 4.5 23.8 1.0
CG A:TYR71 4.5 44.1 1.0
CD1 A:TYR71 4.6 44.5 1.0
CG A:PHE108 4.6 25.0 1.0
F1 A:0B5509 4.7 31.5 1.0

Fluorine binding site 2 out of 5 in 5ygx

Go back to Fluorine Binding Sites List in 5ygx
Fluorine binding site 2 out of 5 in the Structure of BACE1 in Complex with N-(3-((4R,5R,6S)-2-Amino-6-(1,1- Difluoroethyl)-5-Fluoro-4-Methyl-5,6-Dihydro-4H-1,3-Oxazin-4-Yl)-4- Fluorophenyl)-5-(Fluoromethoxy)Pyrazine-2-Carboxamide


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 2 of Structure of BACE1 in Complex with N-(3-((4R,5R,6S)-2-Amino-6-(1,1- Difluoroethyl)-5-Fluoro-4-Methyl-5,6-Dihydro-4H-1,3-Oxazin-4-Yl)-4- Fluorophenyl)-5-(Fluoromethoxy)Pyrazine-2-Carboxamide within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F509

b:31.5
occ:1.00
 F1 A:0B5509 0.0 31.5 1.0
C4 A:0B5509 1.3 30.1 1.0
F2 A:0B5509 2.2 30.6 1.0
C3 A:0B5509 2.3 27.1 1.0
C5 A:0B5509 2.4 29.3 1.0
C2 A:0B5509 2.9 26.0 1.0
O A:HOH628 3.3 53.4 1.0
F A:0B5509 3.3 27.6 1.0
O A:0B5509 3.6 26.2 1.0
CD1 A:TYR71 3.6 44.5 1.0
CG A:TYR71 3.9 44.1 1.0
CB A:TYR71 4.0 45.2 1.0
C1 A:0B5509 4.3 25.4 1.0
CE1 A:TYR71 4.4 43.2 1.0
C7 A:0B5509 4.7 25.0 1.0
O A:HOH802 4.7 48.1 1.0
F4 A:0B5509 4.7 25.6 1.0
C6 A:0B5509 4.7 24.1 1.0
CD2 A:TYR71 4.8 43.5 1.0
C18 A:0B5509 4.9 25.2 1.0
O A:HOH712 4.9 37.1 1.0

Fluorine binding site 3 out of 5 in 5ygx

Go back to Fluorine Binding Sites List in 5ygx
Fluorine binding site 3 out of 5 in the Structure of BACE1 in Complex with N-(3-((4R,5R,6S)-2-Amino-6-(1,1- Difluoroethyl)-5-Fluoro-4-Methyl-5,6-Dihydro-4H-1,3-Oxazin-4-Yl)-4- Fluorophenyl)-5-(Fluoromethoxy)Pyrazine-2-Carboxamide


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 3 of Structure of BACE1 in Complex with N-(3-((4R,5R,6S)-2-Amino-6-(1,1- Difluoroethyl)-5-Fluoro-4-Methyl-5,6-Dihydro-4H-1,3-Oxazin-4-Yl)-4- Fluorophenyl)-5-(Fluoromethoxy)Pyrazine-2-Carboxamide within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F509

b:30.6
occ:1.00
 F2 A:0B5509 0.0 30.6 1.0
C4 A:0B5509 1.3 30.1 1.0
F1 A:0B5509 2.2 31.5 1.0
C5 A:0B5509 2.3 29.3 1.0
C3 A:0B5509 2.3 27.1 1.0
O A:0B5509 2.7 26.2 1.0
O A:HOH712 3.5 37.1 1.0
O A:HOH748 3.7 36.3 1.0
C2 A:0B5509 3.7 26.0 1.0
C6 A:0B5509 4.2 24.1 1.0
F A:0B5509 4.2 27.6 1.0
O A:HOH628 4.5 53.4 1.0
OG1 A:THR231 4.5 25.5 1.0
C1 A:0B5509 4.8 25.4 1.0
O A:HOH763 4.9 37.7 1.0
N1 A:0B5509 4.9 23.9 1.0
N A:0B5509 4.9 22.9 1.0

Fluorine binding site 4 out of 5 in 5ygx

Go back to Fluorine Binding Sites List in 5ygx
Fluorine binding site 4 out of 5 in the Structure of BACE1 in Complex with N-(3-((4R,5R,6S)-2-Amino-6-(1,1- Difluoroethyl)-5-Fluoro-4-Methyl-5,6-Dihydro-4H-1,3-Oxazin-4-Yl)-4- Fluorophenyl)-5-(Fluoromethoxy)Pyrazine-2-Carboxamide


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 4 of Structure of BACE1 in Complex with N-(3-((4R,5R,6S)-2-Amino-6-(1,1- Difluoroethyl)-5-Fluoro-4-Methyl-5,6-Dihydro-4H-1,3-Oxazin-4-Yl)-4- Fluorophenyl)-5-(Fluoromethoxy)Pyrazine-2-Carboxamide within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F509

b:27.6
occ:1.00
 F A:0B5509 0.0 27.6 1.0
C2 A:0B5509 1.4 26.0 1.0
C1 A:0B5509 2.3 25.4 1.0
C3 A:0B5509 2.4 27.1 1.0
C A:0B5509 2.7 24.0 1.0
N1 A:0B5509 2.9 23.9 1.0
O A:0B5509 3.0 26.2 1.0
C4 A:0B5509 3.0 30.1 1.0
C5 A:0B5509 3.0 29.3 1.0
CE1 A:TYR71 3.0 43.2 1.0
C6 A:0B5509 3.1 24.1 1.0
F1 A:0B5509 3.3 31.5 1.0
CD1 A:TYR71 3.5 44.5 1.0
C7 A:0B5509 3.7 25.0 1.0
C2 A:GOL504 3.8 68.6 1.0
CZ A:TYR71 3.8 42.7 1.0
O2 A:GOL504 4.1 61.7 1.0
F4 A:0B5509 4.1 25.6 1.0
OH A:TYR71 4.2 48.5 1.0
N A:0B5509 4.2 22.9 1.0
F2 A:0B5509 4.2 30.6 1.0
C18 A:0B5509 4.4 25.2 1.0
O1 A:GOL504 4.4 61.5 1.0
O3 A:GOL504 4.5 74.5 1.0
CG A:TYR71 4.6 44.1 1.0
C1 A:GOL504 4.6 65.4 1.0
CB A:SER35 4.7 20.0 1.0
C8 A:0B5509 4.7 24.4 1.0
OD2 A:ASP32 4.8 22.0 1.0
C3 A:GOL504 4.8 72.6 1.0
CE2 A:TYR71 4.8 43.7 1.0
O A:GLY34 4.9 22.7 1.0

Fluorine binding site 5 out of 5 in 5ygx

Go back to Fluorine Binding Sites List in 5ygx
Fluorine binding site 5 out of 5 in the Structure of BACE1 in Complex with N-(3-((4R,5R,6S)-2-Amino-6-(1,1- Difluoroethyl)-5-Fluoro-4-Methyl-5,6-Dihydro-4H-1,3-Oxazin-4-Yl)-4- Fluorophenyl)-5-(Fluoromethoxy)Pyrazine-2-Carboxamide


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 5 of Structure of BACE1 in Complex with N-(3-((4R,5R,6S)-2-Amino-6-(1,1- Difluoroethyl)-5-Fluoro-4-Methyl-5,6-Dihydro-4H-1,3-Oxazin-4-Yl)-4- Fluorophenyl)-5-(Fluoromethoxy)Pyrazine-2-Carboxamide within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F509

b:32.9
occ:1.00
 F3 A:0B5509 0.0 32.9 1.0
C14 A:0B5509 1.4 29.9 1.0
O1 A:0B5509 2.3 28.0 1.0
O A:HOH739 2.9 40.8 1.0
C13 A:0B5509 3.0 27.3 1.0
N A:GLY13 3.1 24.5 1.0
N4 A:0B5509 3.1 28.2 1.0
CA A:GLY13 3.4 24.1 1.0
N A:GLY11 3.5 31.7 1.0
N A:GLN12 3.7 26.2 1.0
CE2 A:TYR14 3.8 24.5 1.0
CA A:GLY11 3.8 29.1 1.0
C A:GLY11 4.0 26.6 1.0
O A:LYS9 4.2 33.7 1.0
C12 A:0B5509 4.2 26.6 1.0
C A:GLY13 4.2 24.0 1.0
C A:GLN12 4.2 27.3 1.0
CD2 A:TYR14 4.3 23.2 1.0
NH2 A:ARG307 4.3 30.6 1.0
C15 A:0B5509 4.3 26.9 1.0
O A:GLY13 4.5 25.1 1.0
OG1 A:THR232 4.5 26.3 1.0
C A:SER10 4.6 34.0 1.0
CA A:GLN12 4.6 26.7 1.0
CZ A:TYR14 4.6 25.6 1.0
OE1 A:GLU339 4.6 31.1 1.0
CB A:ALA335 4.7 22.2 1.0
OH A:TYR14 4.8 26.6 1.0
O A:GLY11 4.8 26.3 1.0
CA A:SER10 4.9 36.0 1.0

Reference:

K.Nakahara, K.Fuchino, K.Komano, N.Asada, G.Tadano, T.Hasegawa, T.Yamamoto, Y.Sako, M.Ogawa, C.Unemura, M.Hosono, H.Ito, G.Sakaguchi, S.Ando, S.Ohnishi, Y.Kido, T.Fukushima, D.Dhuyvetter, H.Borghys, H.J.M.Gijsen, Y.Yamano, Y.Iso, K.I.Kusakabe. Discovery of Potent and Centrally Active 6-Substituted 5-Fluoro-1,3-Dihydro-Oxazine Beta-Secretase (BACE1) Inhibitors Via Active Conformation Stabilization J. Med. Chem. V. 61 5525 2018.
ISSN: ISSN 1520-4804
PubMed: 29775538
DOI: 10.1021/ACS.JMEDCHEM.8B00011
Page generated: Thu Aug 1 17:19:41 2024

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