title: Molecular docking to explore the possible binding mode of potential inhibitors of thioredoxin glutathione reductase.
abstract: Praziquantel (PZQ) is the treatment of choice for schistosomiasis, one of the most important but neglected tropical diseases. Recently, however, Schistosoma have exhibited reduced susceptibility to PZQ, and an urgent need to develop new drugs to treat schistosomiasis has emerged. Thioredoxin glutathione reductase (TGR) plays a crucial role in the redox balance of the parasite, combining glutaredoxin (Grx), glutathione reductase and thioredoxin reductase (TR) activities. Several compounds, including oxadiazole 2‑oxides, phosphinic acid amides, isoxazolones and phosphoramidites, have been identified as agents that inhibit TGR from Schistosoma mansoni (smTGR) and exhibit anti‑schistosomal activity. 4‑Phenyl‑1,2,5‑oxadiazole‑3‑carbonitrile‑2‑oxide has also been shown to be active against TGR from Schistosoma japonicum (sjTGR). The binding sites of these inhibitors, however, remain unclear. To explore the binding interactions of these compounds, we selected six compounds to dock into the NADPH binding site, the active site of the TR domain and the Grx active site of both smTGR and sjTGR using AutoDock 4.2.5.1. The results suggested that the most favoured binding site for all compounds in either sjTGR or smTGR was the oxidised glutathione‑binding pocket of the TR domain. Although all of the compounds could fit into the sjTGR site, the inhibition efficiency of these compounds towards sjTGR was marginally lower than it was towards smTGR, suggesting that it would be necessary to design specific inhibitors of TGR for different Schistosoma species. The docking results showed that all compounds docking in smTGR and sjTGR adopted similar binding modes in the TR domain. Two peptide fragments from another subunit, Phe505'‑Leu508' and Pro572'‑Thr577', played a critical role in the interactions with the inhibitors. In conclusion, the present study has revealed binding mechanisms for potential inhibitors of Schistosoma TGRs and could lead to structure‑based ligand design and the development of new anti-schistosomiasis drugs.
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Biology, Jiangsu Second Normal University, Nanjing, Jiangsu 210013, P.R. China.
authors.forename: Weijuan
authors.initials: W
authors.lastname: Hua
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Jiahuang
authors.initials: J
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Zichun
authors.initials: Z
authors.lastname: Hua
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000737:chemistry*; D001665:Binding Sites; D004791:Enzyme Inhibitors; D019803:Glutathione Disulfide; D015801:Helminth Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007555:Isoxazoles / Q000737:chemistry*; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009249:NADP / Q000737:chemistry; D010069:Oxadiazoles / Q000737:chemistry*; D010084:Oxidation-Reduction; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D012549:Schistosoma japonicum / Q000737:chemistry* / Q000201:enzymology; D012550:Schistosoma mansoni / Q000737:chemistry* / Q000201:enzymology; D013045:Species Specificity; D040681:Structural Homology, Protein
chemical_list: D000871:Anthelmintics; D004791:Enzyme Inhibitors; D015801:Helminth Proteins; D007555:Isoxazoles; D009097:Multienzyme Complexes; D010069:Oxadiazoles; D009249:NADP; D009247:NADH, NADPH Oxidoreductases; C466433:thioredoxin glutathione reductase; D019803:Glutathione Disulfide