title: Investigation of a potential mechanism for the inhibition of SmTGR by Auranofin and its implications for Plasmodium falciparum inhibition.
abstract: Schistosoma mansoni and Plasmodium falciparum are pathogen parasites that spend part of their lives in the blood stream of the human host and are therefore heavily exposed to fluxes of toxic reactive oxygen species (ROS). SmTGR, an essential enzyme of the S. mansoni ROS detoxification machinery, is known to be inhibited by Auranofin although the inhibition mechanism has not been completely clarified. Auranofin also kills P. falciparum, even if its molecular targets are unknown. Here, we used computational and docking techniques to investigate the molecular mechanism of interaction between SmTGR and Auranofin. Furthermore, we took advantage of the homology relationship and of docking studies to assess if PfTR, the SmTGR malaria parasite homologue, can be a putative target for Auranofin. Our findings support a recently hypothesized molecular mechanism of inhibition for SmTGR and suggest that PfTR is indeed a possible and attractive drug target in P. falciparum.
authors.affiliation: Department of Physics, Sapienza University of Rome, Rome, Italy.
authors.forename: Antonia
authors.initials: A
authors.lastname: Caroli
authors.forename: Silvia
authors.initials: S
authors.lastname: Simeoni
authors.forename: Rosalba
authors.initials: R
authors.lastname: Lepore
authors.forename: Anna
authors.initials: A
authors.lastname: Tramontano
authors.forename: Allegra
authors.initials: A
authors.lastname: Via
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D001310:Auranofin / Q000737:chemistry / Q000494:pharmacology*; D008956:Models, Chemical; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology*; D017433:Protein Structure, Secondary; D012550:Schistosoma mansoni / Q000201:enzymology
chemical_list: D000962:Antimalarials; D009097:Multienzyme Complexes; D001310:Auranofin; D009247:NADH, NADPH Oxidoreductases; C466433:thioredoxin glutathione reductase