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Zinc 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
Magnesium (Mg) 3 atoms

Zinc Binding Sites:

The binding sites of Zinc 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 Zinc atom.
In total 3 binding sites of Zinc 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 Zinc binding site number: 1; 2; 3;

Zinc binding site 1 out of 3 in 5vp0

Go back to Zinc Binding Sites List in 5vp0
Zinc 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 Zinc with other atoms in the Zn 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:Zn1001

b:31.1
occ:1.00
 OD2 A:ASP697 2.1 22.4 1.0
OD1 A:ASP808 2.1 32.6 1.0
NE2 A:HIS660 2.2 26.4 1.0
NE2 A:HIS696 2.2 28.4 1.0
O A:HOH1133 2.4 37.7 1.0
CD2 A:HIS696 3.0 27.0 1.0
CG A:ASP808 3.1 31.4 1.0
CD2 A:HIS660 3.1 26.9 1.0
CG A:ASP697 3.2 22.5 1.0
CE1 A:HIS660 3.2 26.3 1.0
OD2 A:ASP808 3.3 32.4 1.0
CE1 A:HIS696 3.3 28.9 1.0
OD1 A:ASP697 3.7 22.1 1.0
MG A:MG1002 3.8 31.5 1.0
O A:HOH1107 4.2 34.9 1.0
CG A:HIS696 4.2 28.2 1.0
CG A:HIS660 4.3 25.7 1.0
CD2 A:HIS656 4.3 32.4 1.0
CB A:ASP697 4.3 23.5 1.0
ND1 A:HIS660 4.3 26.2 1.0
ND1 A:HIS696 4.3 30.2 1.0
O A:HOH1134 4.3 26.3 1.0
CB A:ASP808 4.5 32.7 1.0
NE2 A:HIS656 4.6 34.0 1.0
CG2 A:VAL664 4.7 31.3 1.0
O A:HOH1101 4.8 22.0 1.0
CA A:ASP808 4.8 31.7 1.0
O A:ASP808 4.9 29.8 1.0

Zinc binding site 2 out of 3 in 5vp0

Go back to Zinc Binding Sites List in 5vp0
Zinc 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 Zinc with other atoms in the Zn 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:Zn1001

b:31.4
occ:1.00
 OD2 B:ASP697 2.1 27.1 1.0
NE2 B:HIS660 2.2 27.1 1.0
OD1 B:ASP808 2.2 30.8 1.0
NE2 B:HIS696 2.3 28.3 1.0
O B:HOH1141 2.3 37.1 1.0
O B:HOH1119 2.5 31.2 1.0
CD2 B:HIS696 3.0 28.2 1.0
CD2 B:HIS660 3.0 27.0 1.0
CG B:ASP808 3.1 31.0 1.0
CG B:ASP697 3.1 28.6 1.0
CE1 B:HIS660 3.2 26.9 1.0
CE1 B:HIS696 3.3 28.4 1.0
OD2 B:ASP808 3.4 36.5 1.0
OD1 B:ASP697 3.7 29.8 1.0
O B:HOH1113 4.0 27.5 1.0
MG B:MG1002 4.1 32.6 1.0
O B:HOH1126 4.2 22.0 1.0
CG B:HIS660 4.2 26.6 1.0
CG B:HIS696 4.2 29.4 1.0
CD2 B:HIS656 4.3 32.8 1.0
ND1 B:HIS660 4.3 26.9 1.0
CB B:ASP697 4.3 28.6 1.0
ND1 B:HIS696 4.4 28.6 1.0
CB B:ASP808 4.5 30.6 1.0
NE2 B:HIS656 4.5 33.5 1.0
CG2 B:VAL664 4.8 31.7 1.0
O B:HOH1102 4.8 20.0 1.0
CA B:ASP808 4.9 29.5 1.0
O B:ASP808 4.9 30.9 1.0

Zinc binding site 3 out of 3 in 5vp0

Go back to Zinc Binding Sites List in 5vp0
Zinc 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 Zinc with other atoms in the Zn 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:Zn1001

b:33.0
occ:1.00
 OD2 C:ASP697 2.1 28.0 1.0
OD1 C:ASP808 2.2 32.2 1.0
NE2 C:HIS660 2.2 31.8 1.0
NE2 C:HIS696 2.2 31.2 1.0
O C:HOH1123 2.3 35.0 1.0
O C:HOH1106 2.5 26.3 1.0
CD2 C:HIS696 3.0 30.3 1.0
CD2 C:HIS660 3.1 32.4 1.0
CG C:ASP808 3.1 32.8 1.0
CG C:ASP697 3.1 30.6 1.0
CE1 C:HIS660 3.2 32.6 1.0
CE1 C:HIS696 3.3 30.9 1.0
OD2 C:ASP808 3.3 33.4 1.0
OD1 C:ASP697 3.7 32.7 1.0
O C:HOH1110 4.1 27.8 1.0
MG C:MG1002 4.1 32.5 1.0
CG C:HIS696 4.2 31.2 1.0
CG C:HIS660 4.2 32.5 1.0
CB C:ASP697 4.3 30.3 1.0
ND1 C:HIS660 4.3 33.0 1.0
ND1 C:HIS696 4.3 31.3 1.0
CD2 C:HIS656 4.3 31.3 1.0
O C:HOH1121 4.3 31.8 1.0
CB C:ASP808 4.5 31.7 1.0
NE2 C:HIS656 4.6 33.0 1.0
CG2 C:VAL664 4.7 30.3 1.0
CA C:ASP808 4.9 31.4 1.0
O C:HOH1103 4.9 25.4 1.0
O C:ASP808 4.9 32.9 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 Oct 28 13:19:03 2024

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