In
all the living systems, reactive oxygen species (ROS) metabolism
provides resistance against internal and external oxidative stresses.
Auranofin (AF), an FDA-approved gold [Au(I)]-conjugated drug, is known
to selectively target thiol-reductases, key enzymes involved in ROS
metabolism. AF has been successfully tested for its inhibitory activity
through biochemical studies, both in vitro and in vivo, against a
diverse range of pathogens including protozoa, nematodes, bacteria,
and so forth. Cocrystal structures of thiol-reductases complexed with
AF revealed that Au(I) was coordinately linked to catalytic cysteines,
but the mechanism of transfer of Au(I) from AF to catalytic cysteines
still remains unknown. In this study, we have employed computational
approaches to understand the interaction of AF with thiol-reductases
of selected human pathogens. A similar network of interactions of
AF was observed in all the studied enzymes. Also, we have shown that
tailor-made analogues of AF can be designed against selective thiol-reductases
for targeted inhibition. Molecular dynamics studies show that the
AF-intermediates, tetraacetylthioglucose (TAG)-gold, and triethylphosphine
(TP)-gold, coordinately linked to one of catalytic cysteines, remain
stable in the binding pocket of thiol-reductases for
Leishmania infantum
and
Plasmodium
falciparum
(PfTrxR). This suggests that the TP and
TAG moieties of AF may be sequentially eliminated during the transfer
of Au(I) to catalytic cysteines of the receptor.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.