Dynamic basis for Auranofin drug recognition by thiol-reductases of human pathogens, and intermediate coordinated adduct formation with catalytic cysteine residues

Sreeragh, Sivadas and Eerappa, Rajakumara (2018) Dynamic basis for Auranofin drug recognition by thiol-reductases of human pathogens, and intermediate coordinated adduct formation with catalytic cysteine residues. Masters thesis, Indian Institute of Technology Hyderabad.

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Abstract

Reactive oxygen species (ROS) metabolism, a major cellular process in all the living systems, pro-vides resistance against internal and external oxidative stress. Auranofin (AF), a FDA approved gold [Au(I)] conjugated anti-rheumatic drug, is known to selectively target thiol-reductases, key enzymes involved in ROS metabolism. Since FDA approval, AF has been successfully tested through biochemically, in vitro and in vivo studies, against a diverse range of pathogens including protozoa, nematodes, bacteria, etc. Co-crystal structures of thiol-reductases like, trypanothione reductase of Leishmania infanum (LiTryR), thioredoxin-glutathione reductase of Schistosoma mansoni (SmTGR) and thioredoxin reductase of Entamoeba histolytica (EhTrxR), complexed with AF revealed that Au(I) was coordinately linked to catalytic cysteines. The mechanism of transfer of Au(I) from AF to catalytic cysteines is still unknown. In this study, we have employed computational approaches to understand the dynamic nature of interaction of AF and AF-analogs with thiol-reductases of selected human pathogens. Similar network of interaction of AF was observed in all studied enzymes. Docking and computed ΔGbind of AF-analogs showed that tailor-made analogs can be designed against selective thiol-reductases for targeted inhibition. The stability of AF-intermediates, TAG-gold and TP-gold, coordinately linked to one of catalytic cysteines in the binding pocket of LiTryR and TrxR of Plasmodium falciparum (PfTrxR), during molecular dynamics simulation suggests the TP and TAG moieties of AF may be sequentially eliminated during transfer of Au(I) to catalytic cysteines of the receptor.

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