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PDBsum entry 6pf5
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Transferase/transferase inhibitor
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PDB id
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6pf5
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References listed in PDB file
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Key reference
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Title
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Structure activity relationship towards design of cryptosporidium specific thymidylate synthase inhibitors.
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Authors
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D.J.Czyzyk,
M.Valhondo,
L.Deiana,
J.Tirado-Rives,
W.L.Jorgensen,
K.S.Anderson.
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Ref.
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Eur J Med Chem, 2019,
183,
111673.
[DOI no: ]
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PubMed id
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Abstract
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Cryptosporidiosis is a human gastrointestinal disease caused by protozoans of
the genus Cryptosporidium, which can be fatal in immunocompromised individuals.
The essential enzyme, thymidylate synthase (TS), is responsible for de novo
synthesis of deoxythymidine monophosphate. The TS active site is relatively
conserved between Cryptosporidium and human enzymes. In previous work, we
identified compound 1,
(2-amino-4-oxo-4,7-dihydro-pyrrolo[2,3-d]pyrimidin-methyl-phenyl-l-glutamic
acid), as a promising selective Cryptosporidium hominis TS (ChTS) inhibitor. In
the present study, we explore the structure-activity relationship around 1
glutamate moiety by synthesizing and biochemically evaluating the inhibitory
activity of analogues against ChTS and human TS (hTS). X-Ray crystal structures
were obtained for compounds bound to both ChTS and hTS. We establish the
importance of the 2-phenylacetic acid moiety methylene linker in optimally
positioning compounds 23, 24, and 25 within the active site. Moreover, through
the comparison of structural data for 5, 14, 15, and 23 bound in both ChTS and
hTS identified that active site rigidity is a driving force in determining
inhibitor selectivity.
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