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Zinc 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
Magnesium (Mg) 4 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 5vp1). 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: 5vp1:
Jump to Zinc binding site number: 1; 2; 3;

Zinc binding site 1 out of 3 in 5vp1

Go back to Zinc Binding Sites List in 5vp1
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:23.8
occ:1.00
 OD2 A:ASP697 2.0 17.6 1.0
OD1 A:ASP808 2.1 21.1 1.0
NE2 A:HIS660 2.2 19.7 1.0
NE2 A:HIS696 2.2 19.6 1.0
O A:HOH1110 2.3 23.6 1.0
O A:HOH1116 2.5 23.5 1.0
CD2 A:HIS696 3.0 19.2 1.0
CD2 A:HIS660 3.1 19.8 1.0
CG A:ASP697 3.1 17.9 1.0
CG A:ASP808 3.1 20.6 1.0
CE1 A:HIS660 3.2 20.0 1.0
CE1 A:HIS696 3.2 20.0 1.0
OD2 A:ASP808 3.4 20.8 1.0
OD1 A:ASP697 3.7 17.8 1.0
MG A:MG1002 4.0 22.6 1.0
O A:HOH1173 4.2 20.5 1.0
CD2 A:HIS656 4.2 21.1 1.0
O A:HOH1118 4.2 24.3 1.0
CG A:HIS696 4.2 19.4 1.0
CB A:ASP697 4.3 18.6 1.0
CG A:HIS660 4.3 20.5 1.0
ND1 A:HIS660 4.3 20.3 1.0
ND1 A:HIS696 4.3 20.6 1.0
NE2 A:HIS656 4.4 21.8 1.0
CB A:ASP808 4.5 20.3 1.0
O A:HOH1103 4.7 20.0 1.0
CG2 A:VAL664 4.7 20.6 1.0
CA A:ASP808 4.8 20.4 1.0
O A:ASP808 4.9 20.4 1.0

Zinc binding site 2 out of 3 in 5vp1

Go back to Zinc Binding Sites List in 5vp1
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:25.0
occ:1.00
 OD2 B:ASP697 2.0 19.1 1.0
NE2 B:HIS660 2.1 18.7 1.0
OD1 B:ASP808 2.1 21.3 1.0
NE2 B:HIS696 2.2 20.5 1.0
O B:HOH1111 2.4 24.5 1.0
O B:HOH1152 2.5 21.8 1.0
CD2 B:HIS696 3.1 21.0 1.0
CD2 B:HIS660 3.1 19.2 1.0
CG B:ASP697 3.1 19.4 1.0
CG B:ASP808 3.1 22.0 1.0
CE1 B:HIS660 3.2 18.6 1.0
CE1 B:HIS696 3.2 21.1 1.0
OD2 B:ASP808 3.4 22.6 1.0
OD1 B:ASP697 3.6 19.9 1.0
MG B:MG1002 4.1 22.2 1.0
O B:HOH1126 4.2 18.2 1.0
CD2 B:HIS656 4.2 22.6 1.0
CG B:HIS696 4.2 21.1 1.0
O B:HOH1163 4.2 19.4 1.0
CG B:HIS660 4.2 19.2 1.0
CB B:ASP697 4.2 19.4 1.0
ND1 B:HIS660 4.2 18.8 1.0
ND1 B:HIS696 4.3 20.7 1.0
NE2 B:HIS656 4.4 22.8 1.0
CB B:ASP808 4.5 22.0 1.0
O B:HOH1102 4.7 18.8 1.0
CG2 B:VAL664 4.7 21.5 1.0
CA B:ASP808 4.9 22.2 1.0
O B:ASP808 4.9 21.8 1.0

Zinc binding site 3 out of 3 in 5vp1

Go back to Zinc Binding Sites List in 5vp1
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:24.3
occ:1.00
 OD2 C:ASP697 2.0 20.2 1.0
NE2 C:HIS660 2.2 20.2 1.0
OD1 C:ASP808 2.2 23.1 1.0
NE2 C:HIS696 2.2 22.1 1.0
O C:HOH1144 2.4 20.0 1.0
O C:HOH1103 2.5 21.9 1.0
CD2 C:HIS696 3.0 21.7 1.0
CG C:ASP697 3.1 20.6 1.0
CD2 C:HIS660 3.1 21.0 1.0
CG C:ASP808 3.1 22.4 1.0
CE1 C:HIS660 3.2 20.8 1.0
CE1 C:HIS696 3.2 22.2 1.0
OD2 C:ASP808 3.4 24.6 1.0
OD1 C:ASP697 3.6 20.7 1.0
MG C:MG1002 4.0 21.8 1.0
O C:HOH1129 4.1 21.5 1.0
O C:HOH1154 4.2 17.0 1.0
CG C:HIS696 4.2 21.9 1.0
CB C:ASP697 4.2 20.9 1.0
CD2 C:HIS656 4.2 21.4 1.0
ND1 C:HIS696 4.2 22.2 1.0
CG C:HIS660 4.2 21.4 1.0
ND1 C:HIS660 4.3 21.5 1.0
NE2 C:HIS656 4.4 21.5 1.0
CB C:ASP808 4.5 21.8 1.0
O C:HOH1102 4.7 18.4 1.0
CG2 C:VAL664 4.8 22.1 1.0
CA C:ASP808 4.9 21.2 1.0
O C:ASP808 5.0 21.3 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 Oct 28 13:19:03 2024

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