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PDBsum entry 6f23
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PDB id:
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Hydrolase
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Title:
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Complex between mth1 and compound 16 (a 4-amino-7-azaindole derivative)
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Structure:
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7,8-dihydro-8-oxoguanine triphosphatase. Chain: a, b. Synonym: 2-hydroxy-datp diphosphatase,8-oxo-dgtpase,nucleoside diphosphate-linked moiety x motif 1,nudix motif 1. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Variant: isoform p18. Gene: nudt1, mth1. Expressed in: escherichia coli. Expression_system_taxid: 562.
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Resolution:
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1.84Å
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R-factor:
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0.223
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R-free:
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0.259
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Authors:
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J.Viklund,L.Tresaugues,A.Talagas,M.Andersson,U.Ericsson,R.Forsblom, T.Ginman,K.Hallberg,J.Lindstrom,L.Persson,C.Silvander,F.Rahm
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Key ref:
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F.Rahm
et al.
(2018).
Creation of a Novel Class of Potent and Selective MutT Homologue 1 (MTH1) Inhibitors Using Fragment-Based Screening and Structure-Based Drug Design.
J Med Chem,
61,
2533-2551.
PubMed id:
DOI:
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Date:
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23-Nov-17
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Release date:
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07-Mar-18
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PROCHECK
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Headers
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References
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P36639
(8ODP_HUMAN) -
Oxidized purine nucleoside triphosphate hydrolase from Homo sapiens
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Seq:
Struc:
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156 a.a.
159 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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Enzyme class 2:
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E.C.3.6.1.-
- ?????
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Enzyme class 3:
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E.C.3.6.1.56
- 2-hydroxy-dATP diphosphatase.
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Reaction:
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2-oxo-dATP + H2O = 2-oxo-dAMP + diphosphate + H+
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2-oxo-dATP
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+
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H2O
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=
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2-oxo-dAMP
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+
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diphosphate
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+
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H(+)
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Note, where more than one E.C. class is given (as above), each may
correspond to a different protein domain or, in the case of polyprotein
precursors, to a different mature protein.
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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J Med Chem
61:2533-2551
(2018)
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PubMed id:
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Creation of a Novel Class of Potent and Selective MutT Homologue 1 (MTH1) Inhibitors Using Fragment-Based Screening and Structure-Based Drug Design.
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F.Rahm,
J.Viklund,
L.Trésaugues,
M.Ellermann,
A.Giese,
U.Ericsson,
R.Forsblom,
T.Ginman,
J.Günther,
K.Hallberg,
J.Lindström,
L.B.Persson,
C.Silvander,
A.Talagas,
L.Díaz-Sáez,
O.Fedorov,
K.V.M.Huber,
I.Panagakou,
P.Siejka,
M.Gorjánácz,
M.Bauser,
M.Andersson.
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ABSTRACT
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Recent literature has both suggested and questioned MTH1 as a novel cancer
target. BAY-707 was just published as a target validation small molecule probe
for assessing the effects of pharmacological inhibition of MTH1 on tumor cell
survival, both in vitro and in vivo. (1) In this report, we describe the
medicinal chemistry program creating BAY-707, where fragment-based methods were
used to develop a series of highly potent and selective MTH1 inhibitors. Using
structure-based drug design and rational medicinal chemistry approaches, the
potency was increased over 10,000 times from the fragment starting point while
maintaining high ligand efficiency and drug-like properties.
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