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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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Related in: MedlinePlus

Binding modes of native substrates (A) GDS, (B) GSH and (C) NADPH in smTGR (left) and sjTGR (right). Residues contacting substrates (within 0.5 nm) are shown as sticks. Hydogen bonds are represented by dashed green lines. GDS, oxidised glutathione; GSH, glutathione; smTGR, thioredoxin glutathione reductase from Schistosoma mansoni; sjTGR, thioredoxin glutathione reductase from Schistosoma japonicum.
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f2-mmr-12-04-5787: Binding modes of native substrates (A) GDS, (B) GSH and (C) NADPH in smTGR (left) and sjTGR (right). Residues contacting substrates (within 0.5 nm) are shown as sticks. Hydogen bonds are represented by dashed green lines. GDS, oxidised glutathione; GSH, glutathione; smTGR, thioredoxin glutathione reductase from Schistosoma mansoni; sjTGR, thioredoxin glutathione reductase from Schistosoma japonicum.

Mentions: In sjTGR, GDS occupies the same position as in smTGR, except that Leu120 replaces the Lys124 that interacts with GDS in smTGR (Fig. 2A). The remaining residues that form contacts with GDS in sjTGR are the same as those described for smTGR. The estimated free energy of binding of GDS to smTGR is −2.80 kcal/mol, compared with −3.39 kcal/mol for binding to sjTGR (Tables II and III), indicating that GDS binding to sjTGR is more stable than GDS binding to smTGR.


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)

Binding modes of native substrates (A) GDS, (B) GSH and (C) NADPH in smTGR (left) and sjTGR (right). Residues contacting substrates (within 0.5 nm) are shown as sticks. Hydogen bonds are represented by dashed green lines. GDS, oxidised glutathione; GSH, glutathione; 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

f2-mmr-12-04-5787: Binding modes of native substrates (A) GDS, (B) GSH and (C) NADPH in smTGR (left) and sjTGR (right). Residues contacting substrates (within 0.5 nm) are shown as sticks. Hydogen bonds are represented by dashed green lines. GDS, oxidised glutathione; GSH, glutathione; smTGR, thioredoxin glutathione reductase from Schistosoma mansoni; sjTGR, thioredoxin glutathione reductase from Schistosoma japonicum.
Mentions: In sjTGR, GDS occupies the same position as in smTGR, except that Leu120 replaces the Lys124 that interacts with GDS in smTGR (Fig. 2A). The remaining residues that form contacts with GDS in sjTGR are the same as those described for smTGR. The estimated free energy of binding of GDS to smTGR is −2.80 kcal/mol, compared with −3.39 kcal/mol for binding to sjTGR (Tables II and III), indicating that GDS binding to sjTGR is more stable than GDS binding to smTGR.

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