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Magnesium in PDB 5vp0: Discovery of Clinical Candidate N-{(1S)-1-[3-Fluoro-4- (Trifluoromethoxy)Phenyl]-2-Methoxyethyl}-7-Methoxy-2-Oxo-2,3- Dihydropyrido[2,3-B]Pyrazine-4(1H)-Carboxamide (Tak-915), A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor For the Treatment of Cognitive Disorders

Enzymatic activity of Discovery of Clinical Candidate N-{(1S)-1-[3-Fluoro-4- (Trifluoromethoxy)Phenyl]-2-Methoxyethyl}-7-Methoxy-2-Oxo-2,3- Dihydropyrido[2,3-B]Pyrazine-4(1H)-Carboxamide (Tak-915), A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor For the Treatment of Cognitive Disorders

All present enzymatic activity of Discovery of Clinical Candidate N-{(1S)-1-[3-Fluoro-4- (Trifluoromethoxy)Phenyl]-2-Methoxyethyl}-7-Methoxy-2-Oxo-2,3- Dihydropyrido[2,3-B]Pyrazine-4(1H)-Carboxamide (Tak-915), A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor For the Treatment of Cognitive Disorders:
3.1.4.17;

Protein crystallography data

The structure of Discovery of Clinical Candidate N-{(1S)-1-[3-Fluoro-4- (Trifluoromethoxy)Phenyl]-2-Methoxyethyl}-7-Methoxy-2-Oxo-2,3- Dihydropyrido[2,3-B]Pyrazine-4(1H)-Carboxamide (Tak-915), A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor For the Treatment of Cognitive Disorders, PDB code: 5vp0 was solved by I.D.Hoffman, with X-Ray Crystallography technique. A brief refinement statistics is given in the table below:

Resolution Low / High (Å) 30.00 / 2.20
Space group C 1 2 1
Cell size a, b, c (Å), α, β, γ (°) 166.704, 74.265, 91.171, 90.00, 109.77, 90.00
R / Rfree (%) 21.1 / 23.6

Other elements in 5vp0:

The structure of Discovery of Clinical Candidate N-{(1S)-1-[3-Fluoro-4- (Trifluoromethoxy)Phenyl]-2-Methoxyethyl}-7-Methoxy-2-Oxo-2,3- Dihydropyrido[2,3-B]Pyrazine-4(1H)-Carboxamide (Tak-915), A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor For the Treatment of Cognitive Disorders also contains other interesting chemical elements:

Fluorine (F) 12 atoms
Zinc (Zn) 3 atoms

Magnesium Binding Sites:

The binding sites of Magnesium atom in the Discovery of Clinical Candidate N-{(1S)-1-[3-Fluoro-4- (Trifluoromethoxy)Phenyl]-2-Methoxyethyl}-7-Methoxy-2-Oxo-2,3- Dihydropyrido[2,3-B]Pyrazine-4(1H)-Carboxamide (Tak-915), A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor For the Treatment of Cognitive Disorders (pdb code 5vp0). This binding sites where shown within 5.0 Angstroms radius around Magnesium atom.
In total 3 binding sites of Magnesium where determined in the Discovery of Clinical Candidate N-{(1S)-1-[3-Fluoro-4- (Trifluoromethoxy)Phenyl]-2-Methoxyethyl}-7-Methoxy-2-Oxo-2,3- Dihydropyrido[2,3-B]Pyrazine-4(1H)-Carboxamide (Tak-915), A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor For the Treatment of Cognitive Disorders, PDB code: 5vp0:
Jump to Magnesium binding site number: 1; 2; 3;

Magnesium binding site 1 out of 3 in 5vp0

Go back to Magnesium Binding Sites List in 5vp0
Magnesium binding site 1 out of 3 in the Discovery of Clinical Candidate N-{(1S)-1-[3-Fluoro-4- (Trifluoromethoxy)Phenyl]-2-Methoxyethyl}-7-Methoxy-2-Oxo-2,3- Dihydropyrido[2,3-B]Pyrazine-4(1H)-Carboxamide (Tak-915), A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor For the Treatment of Cognitive Disorders


Mono view


Stereo pair view

A full contact list of Magnesium with other atoms in the Mg binding site number 1 of Discovery of Clinical Candidate N-{(1S)-1-[3-Fluoro-4- (Trifluoromethoxy)Phenyl]-2-Methoxyethyl}-7-Methoxy-2-Oxo-2,3- Dihydropyrido[2,3-B]Pyrazine-4(1H)-Carboxamide (Tak-915), A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor For the Treatment of Cognitive Disorders within 5.0Å range:
probe atom residue distance (Å) B Occ
A:Mg1002

b:31.5
occ:1.00
 OD1 A:ASP697 2.0 22.1 1.0
O A:HOH1104 2.1 20.0 1.0
O A:HOH1122 2.2 29.4 1.0
O A:HOH1101 2.2 22.0 1.0
O A:HOH1134 2.2 26.3 1.0
CG A:ASP697 3.0 22.5 1.0
OD2 A:ASP697 3.3 22.4 1.0
ZN A:ZN1001 3.8 31.1 1.0
O A:HOH1133 4.0 37.7 1.0
OE2 A:GLU727 4.1 30.5 1.0
CD2 A:HIS696 4.1 27.0 1.0
OG1 A:THR768 4.2 26.5 1.0
O A:HIS696 4.2 29.0 1.0
NE2 A:HIS730 4.2 28.0 1.0
OD2 A:ASP808 4.3 32.4 1.0
CB A:ASP697 4.4 23.5 1.0
CB A:THR768 4.4 28.9 1.0
O A:HOH1125 4.4 40.7 1.0
CD2 A:HIS730 4.5 26.5 1.0
CD2 A:HIS700 4.5 30.5 1.0
NE2 A:HIS700 4.6 30.3 1.0
O A:THR768 4.6 36.2 1.0
NE2 A:HIS656 4.7 34.0 1.0
NE2 A:HIS696 4.7 28.4 1.0
CA A:ASP697 4.7 24.6 1.0
CD2 A:HIS656 4.8 32.4 1.0
C A:HIS696 5.0 26.4 1.0

Magnesium binding site 2 out of 3 in 5vp0

Go back to Magnesium Binding Sites List in 5vp0
Magnesium binding site 2 out of 3 in the Discovery of Clinical Candidate N-{(1S)-1-[3-Fluoro-4- (Trifluoromethoxy)Phenyl]-2-Methoxyethyl}-7-Methoxy-2-Oxo-2,3- Dihydropyrido[2,3-B]Pyrazine-4(1H)-Carboxamide (Tak-915), A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor For the Treatment of Cognitive Disorders


Mono view


Stereo pair view

A full contact list of Magnesium with other atoms in the Mg binding site number 2 of Discovery of Clinical Candidate N-{(1S)-1-[3-Fluoro-4- (Trifluoromethoxy)Phenyl]-2-Methoxyethyl}-7-Methoxy-2-Oxo-2,3- Dihydropyrido[2,3-B]Pyrazine-4(1H)-Carboxamide (Tak-915), A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor For the Treatment of Cognitive Disorders within 5.0Å range:
probe atom residue distance (Å) B Occ
B:Mg1002

b:32.6
occ:1.00
 O B:HOH1123 2.0 25.3 1.0
O B:HOH1106 2.0 27.3 1.0
O B:HOH1119 2.0 31.2 1.0
OD1 B:ASP697 2.1 29.8 1.0
O B:HOH1126 2.2 22.0 1.0
O B:HOH1102 2.2 20.0 1.0
CG B:ASP697 3.2 28.6 1.0
OD2 B:ASP697 3.6 27.1 1.0
OE2 B:GLU727 3.9 38.9 1.0
NE2 B:HIS730 4.1 32.6 1.0
ZN B:ZN1001 4.1 31.4 1.0
O B:HOH1141 4.2 37.1 1.0
OG1 B:THR768 4.3 33.9 1.0
CD2 B:HIS700 4.3 44.3 1.0
CD2 B:HIS730 4.4 32.3 1.0
O B:HIS696 4.4 31.0 1.0
NE2 B:HIS700 4.4 43.3 1.0
CD2 B:HIS696 4.5 28.2 1.0
CB B:ASP697 4.6 28.6 1.0
OD2 B:ASP808 4.6 36.5 1.0
CB B:THR768 4.6 34.5 1.0
NE2 B:HIS656 4.7 33.5 1.0
O B:THR768 4.7 37.6 1.0
CD B:GLU727 4.8 39.0 1.0
CD2 B:HIS656 4.8 32.8 1.0
CA B:ASP697 4.9 29.9 1.0
CG B:GLU727 4.9 37.1 1.0

Magnesium binding site 3 out of 3 in 5vp0

Go back to Magnesium Binding Sites List in 5vp0
Magnesium binding site 3 out of 3 in the Discovery of Clinical Candidate N-{(1S)-1-[3-Fluoro-4- (Trifluoromethoxy)Phenyl]-2-Methoxyethyl}-7-Methoxy-2-Oxo-2,3- Dihydropyrido[2,3-B]Pyrazine-4(1H)-Carboxamide (Tak-915), A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor For the Treatment of Cognitive Disorders


Mono view


Stereo pair view

A full contact list of Magnesium with other atoms in the Mg binding site number 3 of Discovery of Clinical Candidate N-{(1S)-1-[3-Fluoro-4- (Trifluoromethoxy)Phenyl]-2-Methoxyethyl}-7-Methoxy-2-Oxo-2,3- Dihydropyrido[2,3-B]Pyrazine-4(1H)-Carboxamide (Tak-915), A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor For the Treatment of Cognitive Disorders within 5.0Å range:
probe atom residue distance (Å) B Occ
C:Mg1002

b:32.5
occ:1.00
 OD1 C:ASP697 2.0 32.7 1.0
O C:HOH1106 2.1 26.3 1.0
O C:HOH1107 2.1 30.2 1.0
O C:HOH1109 2.1 26.4 1.0
O C:HOH1103 2.2 25.4 1.0
O C:HOH1121 2.3 31.8 1.0
CG C:ASP697 3.1 30.6 1.0
OD2 C:ASP697 3.5 28.0 1.0
OE2 C:GLU727 4.0 38.2 1.0
NE2 C:HIS730 4.0 34.1 1.0
ZN C:ZN1001 4.1 33.0 1.0
O C:HOH1123 4.2 35.0 1.0
O C:HIS696 4.2 29.4 1.0
CD2 C:HIS730 4.2 33.4 1.0
OG1 C:THR768 4.3 30.3 1.0
CD2 C:HIS700 4.3 36.0 1.0
CB C:ASP697 4.4 30.3 1.0
CD2 C:HIS696 4.4 30.3 1.0
NE2 C:HIS700 4.5 36.4 1.0
OD2 C:ASP808 4.6 33.4 1.0
CB C:THR768 4.6 30.9 1.0
NE2 C:HIS656 4.7 33.0 1.0
CA C:ASP697 4.7 31.0 1.0
O C:THR768 4.8 37.9 1.0
CD C:GLU727 4.8 39.7 1.0
CD2 C:HIS656 4.8 31.3 1.0
CG C:GLU727 4.9 36.0 1.0
NE2 C:HIS696 5.0 31.2 1.0

Reference:

S.Mikami, S.Nakamura, T.Ashizawa, I.Nomura, M.Kawasaki, S.Sasaki, H.Oki, H.Kokubo, I.D.Hoffman, H.Zou, N.Uchiyama, K.Nakashima, N.Kamiguchi, H.Imada, N.Suzuki, H.Iwashita, T.Taniguchi. Discovery of Clinical Candidate N-((1S)-1-(3-Fluoro-4-(Trifluoromethoxy)Phenyl) -2-Methoxyethyl)-7-Methoxy-2-Oxo-2,3-Dihydropyrido[2, 3-B]Pyrazine-4(1H)-Carboxamide (Tak-915): A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor For the Treatment of Cognitive Disorders. J. Med. Chem. V. 60 7677 2017.
ISSN: ISSN 1520-4804
PubMed: 28796496
DOI: 10.1021/ACS.JMEDCHEM.7B00807
Page generated: Mon Sep 30 06:15:27 2024

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