Plasmodium falciparum is the most predominant and fatal species of the human malaria parasites and its redox response to oxidative stress involves the enzyme thioredoxin reductase (TrxR). Essential for P. falciparum survival, the enzyme is a promising target for novel antimalarial drugs. A joint experimental and computational study has been carried out to identify PfTrxR inhibitors using molecular modeling and mass spectrometry. The compounds 1,4-napthoquinone (1,4-NQ), bis-(2,4-dinitrophenyl)sulfide (2,4-DNPS), 4-nitrobenzothiadiazole (4-NBT), 3-dimethylaminopropiophenone (3-DAP), menadione (MD), curcumin and demethoxycurcumin (DMC) were tested for antimalarial activity against both chloroquine sensitive (D6) and chloroquine resistant (W2) strains of P. falciparum in cell cultures with a detailed analysis of the predicted binding poses revealing the non-covalent interactions of the molecules to PfTrxR. In silico analysis showed that 2,4-DNPS, 4-NBT, MD, curcumin and DMC interact non-covalently with the inter-subunit region of the homodimeric enzyme. The differences in binding in the active sites of the human and parasite enzymes were assessed to explain the observed experimental selectivity which will be discussed in the presentation.

Characterization of <i>pftrxr</i> inhibitors using in silico methodology and antimalarial assays

248th National Meeting (2014)

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Characterization of pftrxr inhibitors using in silico methodology and antimalarial assays