In our study, we have screened 133 structurally diverse natural compounds from the MEGx® collection of AnalytiCon Discovery and three synthetic hispolone analogs for binding affinity to Plasmodium falciparum thioredoxin reductase (PfTrxR) using an ultrafiltration (UF) and liquid chromatography (LC/MS) based ligand-binding assay newly developed in our laboratory. PfTrxR catalyzes the reduction of thioredoxin (PfTrx) protein. In reduced form, PfTrx is essentially involved in the antioxidative defense and redox regulation of P. falciparum. Nine compounds (yohimbine (1), catharanthine (2), vobasine (3), gnetifolin E (4), quinidine N-oxide (5), 11-hydroxycoronaridine (6), hispolone (7), hispolone methyl ether (8), and hernagine (9)) displayed binding affinity for PfTrxR at 1μM. The ranking order of compound's binding affinities for PfTrxR is 7>6>2>4>5>8>1>9>3. On the other hand, compounds 6, 7, 2 and 8 demonstrated specific binding to the active site of PfTrxR, when ligands were tested in an equimolar mixture of 1 μM.
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