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Thioredoxin reductase (TrxR) has been considered a potential target for cancer chemotherapy. It acts by controlling the redox homeostasis of human cells and, therefore, interfering in its function may trigger apoptosis, which is a crucial tumor suppression mechanism. Despite the great effort in the search for TrxR inhibitors, none was approved for human therapy. In the present study a virtual screening for natural organic compounds is discussed for a set of 72 compounds with known IC-50 for TrxR inhibition. The results suggest the Pleurotin, a naphthoquinone obtained from  Hohenbuehelia grisea  fungus, as a potential TrxR inhibitor, which acts by binding to the active site of the enzyme, between the N- and C-terminal domains. The presence of the ligand blocks the approximation of the C-terminal arm to the N-terminal, which is an essential step of the enzyme function. Besides, the two equivalent binding sites of TrxR were explored, by docking two ligands simultaneously. The results indicate that both sites have an allosteric correlation and, the presence of the ligand in one site may interfere, or even prevent, the binding of the second ligand at the other site. All these findings are quantitatively discussed based on the analysis of long molecular dynamics trajectories, which provides a full description of the ligand-receptor binding modes, average binding energies and conformational changes. Communicated by Ramaswamy H. Sarma

Analysis of Pleurotin binding to human thioredoxin reductase using docking and molecular dynamics simulation