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Magnesium in PDB 5vp1: 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: 5vp1 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 / 1.86
Space group C 1 2 1
Cell size a, b, c (Å), α, β, γ (°) 165.129, 72.712, 90.061, 90.00, 109.15, 90.00
R / Rfree (%) 22.5 / 24.3

Other elements in 5vp1:

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) 9 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 5vp1). This binding sites where shown within 5.0 Angstroms radius around Magnesium atom.
In total 4 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: 5vp1:
Jump to Magnesium binding site number: 1; 2; 3; 4;

Magnesium binding site 1 out of 4 in 5vp1

Go back to Magnesium Binding Sites List in 5vp1
Magnesium binding site 1 out of 4 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:22.6
occ:1.00
 O A:HOH1103 2.0 20.0 1.0
O A:HOH1143 2.0 19.4 1.0
OD1 A:ASP697 2.1 17.8 1.0
O A:HOH1110 2.1 23.6 1.0
O A:HOH1173 2.1 20.5 1.0
O A:HOH1108 2.2 22.3 1.0
CG A:ASP697 3.1 17.9 1.0
OD2 A:ASP697 3.5 17.6 1.0
ZN A:ZN1001 4.0 23.8 1.0
NE2 A:HIS730 4.0 20.9 1.0
O A:HOH1113 4.1 17.5 1.0
OG1 A:THR768 4.1 20.6 1.0
OE2 A:GLU727 4.2 23.3 1.0
O A:HOH1116 4.2 23.5 1.0
O A:HIS696 4.2 19.6 1.0
CD2 A:HIS730 4.2 20.5 1.0
CD2 A:HIS696 4.3 19.2 1.0
CD2 A:HIS700 4.4 23.3 1.0
CB A:ASP697 4.5 18.6 1.0
CB A:THR768 4.5 21.3 1.0
OD2 A:ASP808 4.5 20.8 1.0
O A:THR768 4.6 21.9 1.0
O A:HOH1138 4.6 40.4 1.0
NE2 A:HIS700 4.6 23.9 1.0
NE2 A:HIS656 4.7 21.8 1.0
CA A:ASP697 4.8 18.9 1.0
NE2 A:HIS696 4.8 19.6 1.0
CG A:GLU727 4.8 21.6 1.0
CD A:GLU727 4.9 22.1 1.0
CD2 A:HIS656 4.9 21.1 1.0
C A:HIS696 5.0 18.7 1.0

Magnesium binding site 2 out of 4 in 5vp1

Go back to Magnesium Binding Sites List in 5vp1
Magnesium binding site 2 out of 4 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
A:Mg1003

b:49.5
occ:1.00
 O A:HOH1180 1.6 32.2 1.0
O A:HOH1137 2.1 28.2 1.0
OE2 A:GLU785 2.2 42.9 1.0
O A:HOH1135 2.3 28.0 1.0
O A:HOH1191 2.3 23.8 1.0
O A:GLU785 2.6 39.6 1.0
CD A:GLU785 3.3 41.5 1.0
C A:GLU785 3.6 38.1 1.0
CA A:GLU785 4.0 37.1 1.0
CG A:GLU785 4.1 40.7 1.0
OE1 A:GLU785 4.1 41.0 1.0
O A:ALA784 4.4 36.6 1.0
O A:HOH1139 4.5 41.0 1.0
CB A:GLU785 4.7 38.2 1.0
N A:VAL786 4.8 37.7 1.0

Magnesium binding site 3 out of 4 in 5vp1

Go back to Magnesium Binding Sites List in 5vp1
Magnesium binding site 3 out of 4 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
B:Mg1002

b:22.2
occ:1.00
 O B:HOH1124 2.0 20.7 1.0
O B:HOH1163 2.1 19.4 1.0
O B:HOH1102 2.1 18.8 1.0
O B:HOH1111 2.1 24.5 1.0
O B:HOH1120 2.1 21.6 1.0
OD1 B:ASP697 2.2 19.9 1.0
CG B:ASP697 3.2 19.4 1.0
OD2 B:ASP697 3.6 19.1 1.0
OE2 B:GLU727 4.0 27.3 1.0
O B:HOH1135 4.1 20.8 1.0
ZN B:ZN1001 4.1 25.0 1.0
NE2 B:HIS730 4.1 22.3 1.0
OG1 B:THR768 4.1 23.3 1.0
O B:HOH1152 4.2 21.8 1.0
CD2 B:HIS730 4.3 22.1 1.0
O B:HIS696 4.3 20.9 1.0
CD2 B:HIS696 4.4 21.0 1.0
CD2 B:HIS700 4.5 25.2 1.0
OD2 B:ASP808 4.5 22.6 1.0
CB B:THR768 4.5 23.6 1.0
O B:THR768 4.6 24.6 1.0
CB B:ASP697 4.6 19.4 1.0
NE2 B:HIS700 4.6 25.5 1.0
NE2 B:HIS656 4.7 22.8 1.0
CG B:GLU727 4.8 24.8 1.0
CD B:GLU727 4.8 26.0 1.0
NE2 B:HIS696 4.9 20.5 1.0
CA B:ASP697 4.9 20.1 1.0
C35 B:9GA1003 4.9 22.9 1.0
CD2 B:HIS656 4.9 22.6 1.0

Magnesium binding site 4 out of 4 in 5vp1

Go back to Magnesium Binding Sites List in 5vp1
Magnesium binding site 4 out of 4 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 4 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:21.8
occ:1.00
 O C:HOH1120 2.0 19.2 1.0
O C:HOH1103 2.0 21.9 1.0
O C:HOH1102 2.1 18.4 1.0
O C:HOH1154 2.1 17.0 1.0
O C:HOH1113 2.2 19.6 1.0
OD1 C:ASP697 2.2 20.7 1.0
CG C:ASP697 3.2 20.6 1.0
OD2 C:ASP697 3.6 20.2 1.0
ZN C:ZN1001 4.0 24.3 1.0
OG1 C:THR768 4.1 22.2 1.0
OE2 C:GLU727 4.1 24.7 1.0
O C:HOH1144 4.1 20.0 1.0
NE2 C:HIS730 4.1 22.9 1.0
O C:HOH1143 4.2 23.0 1.0
O C:HIS696 4.3 22.3 1.0
CD2 C:HIS730 4.3 22.4 1.0
CD2 C:HIS696 4.3 21.7 1.0
CB C:THR768 4.4 21.9 1.0
OD2 C:ASP808 4.4 24.6 1.0
O C:THR768 4.5 24.6 1.0
CD2 C:HIS700 4.5 24.3 1.0
CB C:ASP697 4.6 20.9 1.0
NE2 C:HIS700 4.7 25.1 1.0
CG C:GLU727 4.7 24.4 1.0
NE2 C:HIS656 4.8 21.5 1.0
CD C:GLU727 4.8 25.5 1.0
NE2 C:HIS696 4.9 22.1 1.0
CA C:ASP697 4.9 21.8 1.0
C35 C:9GA1003 4.9 25.9 1.0
CD2 C:HIS656 5.0 21.4 1.0

Reference:

S.Mikami, M.Kawasaki, S.Ikeda, N.Negoro, S.Nakamura, I.Nomura, T.Ashizawa, H.Kokubo, I.D.Hoffman, H.Zou, H.Oki, N.Uchiyama, Y.Hiura, M.Miyamoto, Y.Itou, M.Nakashima, H.Iwashita, T.Taniguchi. Discovery of A Novel Series of Pyrazolo[1,5-A]Pyrimidine-Based Phosphodiesterase 2A Inhibitors Structurally Different From 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), For the Treatment of Cognitive Disorders. Chem. Pharm. Bull. V. 65 1058 2017.
ISSN: ISSN 1347-5223
PubMed: 29093293
DOI: 10.1248/CPB.C17-00564
Page generated: Mon Sep 30 06:15:27 2024

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