Design Dithiocarbamate Inhibitors with Increase Binding Affinity to Indoleamine 2,3-Dioxygenase (IDO)

Posted May 12th, 2010 at 1:39 pm.

Tu-Anh Vu
Mentor: Dr. Judith LaLonde

Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressant enzyme that is the rate-limiting enzyme in the production of quinolinic acid from tryptophan through the kynurenine pathway. Researchers have suggested that tumors can elevate the levels of IDO and use it to facilitate an immune escape. Previous studies have shown that knockout mice without IDO perform better in chemotherapy treatments than mice with IDO. Thus, designing IDO inhibitors may improve patients’ responses to caner treatments. In this study, we will design dithiocarbamate inhibitors with increased binding affinity to IDO. In previously published work, our group has shown that hydroxyl and thiol substitution on the benzyl ring of 4-phenyl-imidazole improve binding affinity. Docking calculations of the dithiocarbamate compounds predict that the dithiocarbamate group binds to the heme iron, while the amino-linked benzyl ring of the dithiocarbamate is buried in the back of the cavity. We will apply lessons learned from the -OH and -SH substitutions of phenyl-imidazole to the dithiocarbamate class of compounds. Computational chemistry methods will be used to vet in silico prototype compounds prior to synthesis. The genetic docking algorithm, Gold, is being used to evaluate twenty various substitutions of the amino-linked benzyl ring of the dithiocarbamate. Computational results will determine the best candidates for synthesis.

Filed under: 2008,LaLonde, Dr. Judith,Vu, Tu-Anh by Ann Dixon

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