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J Biol Chem. 2003 Apr 18;278(16):14092-100. Epub 2003 Jan 29.

A molecular docking strategy identifies Eosin B as a non-active site inhibitor of protozoal bifunctional thymidylate synthase-dihydrofolate reductase.

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Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.


Protozoal parasites are unusual in that their thymidylate synthase (TS) and dihydrofolate reductase (DHFR) enzymes exist on a single polypeptide. In an effort to probe the possibility of substrate channeling between the TS and DHFR active sites and to identify inhibitors specific for bifunctional TS-DHFR, we used molecular docking to screen for inhibitors targeting the shallow groove connecting the two active sites. Eosin B is a 100 microm non-active site inhibitor of Leishmania major TS-DHFR identified by molecular docking. Eosin B slows both the TS and DHFR reaction rates. When Arg-283, a key residue to which eosin B is predicted to bind, is mutated to glutamate, however, eosin B only minimally inhibits the TS-DHFR reaction. Additionally, eosin B was found to be a 180 microm inhibitor of Toxoplasma gondii in both biochemical and cell culture assays.

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