Development of antiviral inhibitor against dengue 2 targeting Ns3 protein: In vitro and in silico significant studies

Praveenkumar, Padmapriya; Fathima, S G; Ramanathan, Giriprasath; Yuvaraj,; A, Khaleefathullah Sheriff; Kaveri, K; Gunasekaran, Palani; Sivagnanam, Uma Tirichurapalli; Thennarasu, Sathiah

doi:10.1016/j.actatropica.2018.08.022

Cited by 11 publications

(8 citation statements)

References 27 publications

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“…Previously discovered small molecule inhibitors of dengue protease are found to bind to the active site, orthosteric site, or allosteric site − of the enzyme. To determine whether the observed inhibition of the proteases by the compounds 1 – 3 is due to binding at the active site or at the orthosteric/allosteric site, we conducted enzyme kinetic analyses by monitoring the enzyme activity and inhibition at varying concentrations of the inhibitor and the substrate (60–4.6 μM).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Dengue Virus Protease by Eugeniin, Isobiflorin, and Biflorin Isolated from the Flower Buds of Syzygium aromaticum (Cloves)

et al. 2019

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Dengue virus (DENV) infections are rampant in tropical and subtropical regions of the world with millions of people at risk. There is still no specific antiviral treatment available against these infections. Amongst the different potential therapeutic targets, DENV protease is considered an important target because of its crucial role in the viral replication cycle. We are reporting here a potent DENV protease inhibitor, eugeniin (3), which has been isolated from cloves, along with two other weaker inhibitors, isobiflorin (1) and biflorin (2). In this study, the IC 50 values of 3 against the proteases of DENV serotype-2 and -3 were found to be 94.7 nM and 7.5 μM, respectively. Mechanistically, the compounds 1−3 exhibited a competitive type of inhibition, which were further substantiated by computational docking and saturation transfer difference (STD) NMR spectroscopy. Atomic-level details of the binding of these molecules at the active site of the protease suggested extensive interactions mediated by a network of hydrogen bonds and hydrophobic contacts. With further evaluation, these inhibitors are highly promising in the context of antiviral therapeutics development against DENV.

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Section: Resultsmentioning

confidence: 99%

Inhibition of Dengue Virus Protease by Eugeniin, Isobiflorin, and Biflorin Isolated from the Flower Buds of Syzygium aromaticum (Cloves)

et al. 2019

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“…The use of natural substances derived from Carica papaya and Euphorbia hirta to treat dengue has been reported in recent studies [26]. Despite numerous in vitro studies conducted over the years, effective dengue inhibitors have yet to be discovered [27]. Computer-aided techniques are becoming more crucial in drug discovery because they help uncover potential therapeutic options quickly from a large pool of possibilities with low failure rates and recall [28].…”

Section: Fig 1 Ns5 Protein Of Dengue Virusmentioning

confidence: 99%

In silico exploration of potent flavonoids for dengue therapeutics

Phunyal,

Adhikari Subin,

Adhikari

2024

Preprint

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Dengue poses a persistent and widespread threat with no effective antiviral drug available till now. Several inhibitors have been developed by targeting the viral non-structural proteins including methyl transferase (NS5) of the dengue virus with possible therapeutic values. In this work, virtual screening, molecular docking, molecular dynamics simulations (200 ns), and assessments of free energy changes to identify potential candidates from a database of flavonoids (ca. 2000) that may have good curative potential from the disease. The binding affinity of flavonoids, namely Genistein-7-glucoside (FLD1), 6’–O-Acetylgenistin (FLD2), 5,6-dihydroxy-2-(4-hydroxyphenyl)-7-[3,4,5-trihydroxy-6-(hydroxymethyl)oxane-2-yl]oxychromen-4-one (FLD3), Glucoliquiritigenin (FLD4), and Chrysin-7-O-glucoronide (FLD5) showed the binding affinities of −10.2, −10.2, −10.1, −10.1, −9.9 kcal/mol, respectively, and possessed better values than that of the native ligand with showed (−7.6 kcal/mol) and diclofenac sodium (−7.3 kcal/mol). Drug-likeness of these compounds was acceptable and no toxicity was hinted by ADMET predictions. The stability of the protein-ligand complexes was accessed from 200 ns molecular dynamics simulation in terms of various geometrical parameters; RMSD, RMSF of residues, Rg, SASA, and H-bond of the protein-ligand complexes. The binding free energy changes of these compounds were calculated by the MM-PBSA solvation model with negative values (less than −38.01±7.53 kcal/mol) indicating the spontaneity of the forward reaction and favorability of the product formation. The geometrical and thermodynamic parameters infer that the flavonoid binds at the orthosteric site of the target protein of DENV-2 and could inhibit its functioning resulting in the prevention of the disease. Overall, this study highlights the anti-DENV activity of five flavonoids, positioning them as promising candidates for further development as antiviral agents against dengue infection.

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“…protease are found to bind to the active site, [16][17][18]44,45] orthosteric site, [25] or allosteric site [46][47][48][49][50][51][52][53] of the protease. To determine the precise mode of binding of the potent inhibitors, ABT263, ABT737, TW37, and AT101, to DENV2 NS2B/NS3 protease, we conducted kinetic analyses by monitoring the protease activity and inhibition at fixed concentrations of inhibitors (0.5 and 2 μM) and varying concentrations of the substrate (60-4.6 μM).…”

Section: Mode Of Inhibitionmentioning

confidence: 99%

Repurposing of investigational cancer drugs: Early phase discovery of dengue virus NS2B/NS3 protease inhibitors

Saleem,

Kousar,

Jiskani

et al. 2023

Archiv der Pharmazie

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Dengue fever is a neglected vector‐borne disease and is more prevalent in Asia. Currently, no specific treatment is available. Given the time and cost of de novo drug discovery and development, an alternative option of drug repurposing is becoming an effective tool. We screened a library of 1127 pharmacologically active, metabolically stable, and structurally diverse small anticancer molecules to identify inhibitors of the dengue virus (DENV) NS2B/NS3 protease. Enzyme kinetics and inhibition data revealed four B‐cell lymphoma 2 inhibitors, that is, ABT263, ABT737, AT101, and TW37, as potent inhibitors of DENV NS2B/NS3 protease, with IC50 values of 0.86, 1.15, 0.81, and 0.89 µM, respectively. Mode of inhibition experiments and computational docking analyses indicated that ABT263 and ABT737 are competitive inhibitors, whereas AT101 and TW37 are noncompetitive inhibitors of the protease. With further evaluation, the identified inhibitors of the DENV NS2B/NS3 protease have the potential to be developed into specific anti‐dengue therapeutics.

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Development of antiviral inhibitor against dengue 2 targeting Ns3 protein: In vitro and in silico significant studies

Cited by 11 publications

References 27 publications

Inhibition of Dengue Virus Protease by Eugeniin, Isobiflorin, and Biflorin Isolated from the Flower Buds of Syzygium aromaticum (Cloves)

Inhibition of Dengue Virus Protease by Eugeniin, Isobiflorin, and Biflorin Isolated from the Flower Buds of Syzygium aromaticum (Cloves)

In silico exploration of potent flavonoids for dengue therapeutics

Repurposing of investigational cancer drugs: Early phase discovery of dengue virus NS2B/NS3 protease inhibitors

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