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PDBsum entry 3jq7
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Oxidoreductase
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PDB id
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3jq7
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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-Based design of pteridine reductase inhibitors targeting african sleeping sickness and the leishmaniases.
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Authors
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L.B.Tulloch,
V.P.Martini,
J.Iulek,
J.K.Huggan,
J.H.Lee,
C.L.Gibson,
T.K.Smith,
C.J.Suckling,
W.N.Hunter.
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Ref.
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J Med Chem, 2010,
53,
221-229.
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PubMed id
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Abstract
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Pteridine reductase (PTR1) is a target for drug development against Trypanosoma
and Leishmania species, parasites that cause serious tropical diseases and for
which therapies are inadequate. We adopted a structure-based approach to the
design of novel PTR1 inhibitors based on three molecular scaffolds. A series of
compounds, most newly synthesized, were identified as inhibitors with
PTR1-species specific properties explained by structural differences between the
T. brucei and L. major enzymes. The most potent inhibitors target T. brucei
PTR1, and two compounds displayed antiparasite activity against the bloodstream
form of the parasite. PTR1 contributes to antifolate drug resistance by
providing a molecular bypass of dihydrofolate reductase (DHFR) inhibition.
Therefore, combining PTR1 and DHFR inhibitors might improve therapeutic
efficacy. We tested two new compounds with known DHFR inhibitors. A synergistic
effect was observed for one particular combination highlighting the potential of
such an approach for treatment of African sleeping sickness.
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