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Molecular docking to explore the possible binding mode of potential inhibitors of thioredoxin glutathione reductase.

Huang J, Hua W, Li J, Hua Z - Mol Med Rep (2015)

Bottom Line: 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.The docking results showed that all compounds docking in smTGR and sjTGR adopted similar binding modes in the TR domain.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.

View Article: PubMed Central - PubMed

Affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, P.R. China.

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.

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Ratios of the free binding energies of the inhibitors to the free binding energies of the native substrates glutathione, oxidised glutathione and NADPH in the corresponding Grx active site, TR active site and NADPH binding site, respectively. (A and B) Docking ratio of test molecules in (A) smTGR and (B) sjTGR. TR, thioredoxin reductase; Grx, glutaredoxin; smTGR, thioredoxin glutathione reductase from Schistosoma mansoni; sjTGR, thioredoxin glutathione reductase from Schistosoma japonicum.
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f3-mmr-12-04-5787: Ratios of the free binding energies of the inhibitors to the free binding energies of the native substrates glutathione, oxidised glutathione and NADPH in the corresponding Grx active site, TR active site and NADPH binding site, respectively. (A and B) Docking ratio of test molecules in (A) smTGR and (B) sjTGR. TR, thioredoxin reductase; Grx, glutaredoxin; smTGR, thioredoxin glutathione reductase from Schistosoma mansoni; sjTGR, thioredoxin glutathione reductase from Schistosoma japonicum.

Mentions: The docking ratios of the test molecules in smTGR are shown in Fig. 3A. All docking ratio values in the TR active cavity were >2.3, higher than those in the Grx domain or the NADPH-binding site. For sjTGR, the values of the docking ratio in the TR active centre were >1.9 (Fig. 3B). These values were generally lower than those for smTGR, indicating that the compounds were less effective sjTGR inhibitors. The data suggested that it is necessary to design effective inhibitors for the specific TGRs from different Schistosoma species.


Molecular docking to explore the possible binding mode of potential inhibitors of thioredoxin glutathione reductase.

Huang J, Hua W, Li J, Hua Z - Mol Med Rep (2015)

Ratios of the free binding energies of the inhibitors to the free binding energies of the native substrates glutathione, oxidised glutathione and NADPH in the corresponding Grx active site, TR active site and NADPH binding site, respectively. (A and B) Docking ratio of test molecules in (A) smTGR and (B) sjTGR. TR, thioredoxin reductase; Grx, glutaredoxin; smTGR, thioredoxin glutathione reductase from Schistosoma mansoni; sjTGR, thioredoxin glutathione reductase from Schistosoma japonicum.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581810&req=5

f3-mmr-12-04-5787: Ratios of the free binding energies of the inhibitors to the free binding energies of the native substrates glutathione, oxidised glutathione and NADPH in the corresponding Grx active site, TR active site and NADPH binding site, respectively. (A and B) Docking ratio of test molecules in (A) smTGR and (B) sjTGR. TR, thioredoxin reductase; Grx, glutaredoxin; smTGR, thioredoxin glutathione reductase from Schistosoma mansoni; sjTGR, thioredoxin glutathione reductase from Schistosoma japonicum.
Mentions: The docking ratios of the test molecules in smTGR are shown in Fig. 3A. All docking ratio values in the TR active cavity were >2.3, higher than those in the Grx domain or the NADPH-binding site. For sjTGR, the values of the docking ratio in the TR active centre were >1.9 (Fig. 3B). These values were generally lower than those for smTGR, indicating that the compounds were less effective sjTGR inhibitors. The data suggested that it is necessary to design effective inhibitors for the specific TGRs from different Schistosoma species.

Bottom Line: 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.The docking results showed that all compounds docking in smTGR and sjTGR adopted similar binding modes in the TR domain.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.

View Article: PubMed Central - PubMed

Affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, Jiangsu 210093, P.R. China.

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.

Show MeSH
Related in: MedlinePlus