&lt;i&gt;In silico&lt;/i&gt; studies for the interaction of tumor necrosis factor-alpha (TNF-α) with different saponins from Vietnamese ginseng (&lt;i&gt;Panax vietnamesis&lt;/i&gt;)

Kim, Oanh Thi Phuong; Le, Manh Duc; Trinh, Hoang X.; Nong, Hai Van

doi:10.2142/biophysico.13.0_173

Cited by 26 publications

(10 citation statements)

References 41 publications

(40 reference statements)

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“…The crystal structure between TNFα and SPD304 places the binding site at the lower part of the pore. Docking studies between this inhibitor and the trimeric form of TNFα showed interactions at the top end of the trimerization interface, proposing that further rearrangements are necessary for accessing the interface core . Our results with the interface mutants are consistent with an interaction at the core of the trimer (Figure ).…”

Section: Discussionsupporting

confidence: 82%

Activity of Tumor Necrosis Factor α Is Modulated by Dynamic Conformational Rearrangements

2017

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The homotrimeric ligand tumor necrosis factor α (TNFα) is a key cytokine and immune regulator; however, when deregulated, it leads to several major chronic inflammatory diseases. Perturbation of the protein-protein interface has proven to be an efficient strategy to inactivate TNFα, but the atomic-resolution mechanism of its inactivation remains poorly understood. Here, we probe the solution structure and dynamics of active and inactive TNFα using NMR spectroscopy. The data reveal that TNFα undergoes motions on different time scales. Furthermore, by site-directed mutagenesis of residues at the trimerization interface and by targeting the interface with a low molecular weight inhibitor, we show that TNFα retains its overall structure and trimeric state. However, upon perturbation, TNFα exhibits increased conformational dynamics spanning from the trimerization interface to the regions mediating receptor binding. These findings provide novel insights into the inactivation mechanism of TNFα and the basis for strategies to target TNFα activity.

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Section: Discussionsupporting

confidence: 82%

Activity of Tumor Necrosis Factor α Is Modulated by Dynamic Conformational Rearrangements

2017

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“…The five best TNFα inhibitors interact with the TNFα homodimer and inhibit the active form of homotrimers. Oanh et al [34] reported that the triterpene saponins had a good binding affinity with protein TNFα and were docked to the pore at the top of the bell or cone shaped TNFα trimer. Mehreen et al [35] also reported that the novel small molecules interacted with TNFα trimer.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel inhibitors for TNFα, TNFR1 and TNFα-TNFR1 complex using pharmacophore-based approaches

Saddala

2019

J Transl Med

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Background Tumor necrosis factor α (TNFα) is a multifunctional cytokine with a potent pro-inflammatory effect. It is a validated therapeutic target molecule for several disorders related to autoimmunity and inflammation. TNFα–TNF receptor-1 (TNFR1) signaling contributes to the pathological processes of these disorders. The current study is focused on finding novel small molecules that can directly bind to TNFα and/or TNFR1, preventing the interaction between TNFα or TNFR1, and regulating downstream signaling pathways. Methods Cheminformatics pipeline (pharmacophore modeling, virtual screening, molecular docking and in silico ADMET analysis) was used to screen for novel TNFα and TNFR1 inhibitors in the Zinc database. The pharmacophore-based models were generated to screen for the best drug like compounds in the Zinc database. Results The 39, 37 and 45 best hit molecules were mapped with the core pharmacophore features of TNFα, TNFR1, and the TNFα–TNFR1 complex respectively. They were further evaluated by molecular docking, protein–ligand interactions and in silico ADMET studies. The molecular docking analysis revealed the binding energies of TNFα, TNFR1 and the TNFα–TNFR1 complex, the basis of which was used to select the top five best binding energy compounds. Furthermore, in silico ADMET studies clearly revealed that all 15 compounds (ZINC09609430, ZINC49467549, ZINC13113075, ZINC39907639, ZINC25251930, ZINC02968981, ZINC09544246, ZINC58047088, ZINC72021182, ZINC08704414, ZINC05462670, ZINC35681945, ZINC23553920, ZINC05328058, and ZINC17206695) satisfied the Lipinski rule of five and had no toxicity. Conclusions The new selective TNFα, TNFR1 and TNFα–TNFR1 complex inhibitors can serve as anti-inflammatory agents and are promising candidates for further research. Electronic supplementary material The online version of this article (10.1186/s12967-019-1965-5) contains supplementary material, which is available to authorized users.

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“…The present molecular docking and interactions or structure based virtual screening of phytoligands and synthetic ligand was done to detect receptor-ligand binding site, which supported by several researchers [59,60]. The receptor TNF-α and phytoligands binding had been carried out with bioactive compounds of several medicinal plants for new drug discovery [59,60,61]. Also, it was studied that crude extract of Avicennia sp.…”

Section: Resultsmentioning

confidence: 91%

Untitled

2019

RJLBPCS

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The objective was to predict toxicity on daphnids, fish and rat oral exposure through quantitative structure activity relationship (QSAR) modelling as well as binding affinity and energy value of common phytochemicals present in Avecennia sp. compared to synthetic drug (Ibuprofen) on tumour necrosis factor-α (TNF-α) through molecular docking and interaction study. The QSAR modelling was done for toxicity evaluation by using T.E.S.T. (Version 4.1) and the virtual screening to know receptor-ligand binding affinity and energy value by using the software, PyRx (Version 0.8). The TNF-α (receptor) was obtained (PDB ID: 2az5) from the European Protein Data Bank (PDBe) and the information on selected fifteen ligands (phytochemicals) and one synthetic ligand (Ibuprofen) were taken from PubChem database. QSAR modelling resulted all the compounds showed toxic to D. magna and P. promelas but non-toxic to rat oral exposure. In the docking result, among established 15 phytocompounds, Lupeol (ligand) was observed favourable binding energy value (-10.7 Kcal/mol) on the TNF-α receptor followed by Taraxerone (-10.1 Kcal/mol) compared to Ibuprofen (-6.7 Kcal/mol). In conclusion, phytoligand Lupeol of Avicennia sp. showed the activity of lead molecule, which may inhibit the activity of TNFα and prevent inflammation. The future study is suggested the toxicological and pharmacological assay to validate the present predictive data.

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<i>In silico</i> studies for the interaction of tumor necrosis factor-alpha (TNF-α) with different saponins from Vietnamese ginseng (<i>Panax vietnamesis</i>)

Cited by 26 publications

References 41 publications

Activity of Tumor Necrosis Factor α Is Modulated by Dynamic Conformational Rearrangements

Activity of Tumor Necrosis Factor α Is Modulated by Dynamic Conformational Rearrangements

Identification of novel inhibitors for TNFα, TNFR1 and TNFα-TNFR1 complex using pharmacophore-based approaches

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