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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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(A) Homology structure of sjTGR dimer. (B) Comparison between the sjTGR homology model and the template of thioredoxin glutathione reductase from Schistosoma mansoni. Colours stand for each model's degree of coincidence, from low to high (from dark to light, respectively). (C) Ramachandran plot of the monomeric sjTGR model and results of protein structure evaluation of the sjTGR model using PROCHECK. TR, thioredoxin reductase; Grx, glutaredoxin; sjTGR, thioredoxin glutathione reductase from Schistosoma japonicum.
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f1-mmr-12-04-5787: (A) Homology structure of sjTGR dimer. (B) Comparison between the sjTGR homology model and the template of thioredoxin glutathione reductase from Schistosoma mansoni. Colours stand for each model's degree of coincidence, from low to high (from dark to light, respectively). (C) Ramachandran plot of the monomeric sjTGR model and results of protein structure evaluation of the sjTGR model using PROCHECK. TR, thioredoxin reductase; Grx, glutaredoxin; sjTGR, thioredoxin glutathione reductase from Schistosoma japonicum.

Mentions: There is 89% identity between the template smTGR (smTGR 2×99) and the sjTGR sequences. Due to the fact that the template sequence lacks the N- and C-terminal SeC tail peptide fragments, the model of sjTGR that was used contained only residues 6–592 (Fig. 1A). The coincidence degree between the sjTGR model and the template is shown in Fig. 1B. The shades of the colours, from dark green to grey, represent the model's degree of coincidence, from low to high. The unmatched region was mainly located at the C-terminal; other regions of the model showed high coincidence with the template (Fig. 1B). The rationality of the stereochemistry in the newly constructed model was evaluated using PROCHECK. The ϕ-ψ plot of the sjTGR dimer is shown in Fig. 1C. With the exception of the Gly and Pro residues, there were 916 amino acids (89.5%) in the most favoured regions and 104 amino acids (10.2%) in additional allowed regions. G-factor values of all dihedral angles were >−0.5, which suggested that the overall structure was reasonably good (Fig. 1C).


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)

(A) Homology structure of sjTGR dimer. (B) Comparison between the sjTGR homology model and the template of thioredoxin glutathione reductase from Schistosoma mansoni. Colours stand for each model's degree of coincidence, from low to high (from dark to light, respectively). (C) Ramachandran plot of the monomeric sjTGR model and results of protein structure evaluation of the sjTGR model using PROCHECK. TR, thioredoxin reductase; Grx, glutaredoxin; 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

f1-mmr-12-04-5787: (A) Homology structure of sjTGR dimer. (B) Comparison between the sjTGR homology model and the template of thioredoxin glutathione reductase from Schistosoma mansoni. Colours stand for each model's degree of coincidence, from low to high (from dark to light, respectively). (C) Ramachandran plot of the monomeric sjTGR model and results of protein structure evaluation of the sjTGR model using PROCHECK. TR, thioredoxin reductase; Grx, glutaredoxin; sjTGR, thioredoxin glutathione reductase from Schistosoma japonicum.
Mentions: There is 89% identity between the template smTGR (smTGR 2×99) and the sjTGR sequences. Due to the fact that the template sequence lacks the N- and C-terminal SeC tail peptide fragments, the model of sjTGR that was used contained only residues 6–592 (Fig. 1A). The coincidence degree between the sjTGR model and the template is shown in Fig. 1B. The shades of the colours, from dark green to grey, represent the model's degree of coincidence, from low to high. The unmatched region was mainly located at the C-terminal; other regions of the model showed high coincidence with the template (Fig. 1B). The rationality of the stereochemistry in the newly constructed model was evaluated using PROCHECK. The ϕ-ψ plot of the sjTGR dimer is shown in Fig. 1C. With the exception of the Gly and Pro residues, there were 916 amino acids (89.5%) in the most favoured regions and 104 amino acids (10.2%) in additional allowed regions. G-factor values of all dihedral angles were >−0.5, which suggested that the overall structure was reasonably good (Fig. 1C).

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