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PDBsum entry 3kjs
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Oxidoreductase,transferase
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PDB id
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3kjs
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References listed in PDB file
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Key reference
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Title
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Synthesis and characterization of potent inhibitors of trypanosoma cruzi dihydrofolate reductase.
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Authors
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N.Schormann,
S.E.Velu,
S.Murugesan,
O.Senkovich,
K.Walker,
B.C.Chenna,
B.Shinkre,
A.Desai,
D.Chattopadhyay.
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Ref.
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Bioorg Med Chem Lett, 2010,
18,
4056-4066.
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PubMed id
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Abstract
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Dihydrofolate reductase (DHFR) of the parasite Trypanosoma cruzi (T. cruzi) is a
potential target for developing drugs to treat Chagas' disease. We have
undertaken a detailed structure-activity study of this enzyme. We report here
synthesis and characterization of six potent inhibitors of the parasitic enzyme.
Inhibitory activity of each compound was determined against T. cruzi and human
DHFR. One of these compounds, ethyl
4-(5-[(2,4-diamino-6-quinazolinyl)methyl]amino-2-methoxyphenoxy)butanoate (6b)
was co-crystallized with the bifunctional dihydrofolate reductase-thymidylate
synthase enzyme of T. cruzi and the crystal structure of the ternary
enzyme:cofactor:inhibitor complex was determined. Molecular docking was used to
analyze the potential interactions of all inhibitors with T. cruzi DHFR and
human DHFR. Inhibitory activities of these compounds are discussed in the light
of enzyme-ligand interactions. Binding affinities of each inhibitor for the
respective enzymes were calculated based on the experimental or docked binding
mode. An estimated 60-70% of the total binding energy is contributed by the
2,4-diaminoquinazoline scaffold.
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