In silico and in vitro studies of potential inhibitors against Dengue viral protein NS5 Methyl Transferase from Ginseng and Notoginseng

Jarerattanachat, Viwan; Boonarkart, Chompunuch; Hannongbua, Supa; Auewarakul, Prasert; Ardkhean, Ruchuta

doi:10.1016/j.jtcme.2022.12.002

Cited by 10 publications

(7 citation statements)

References 61 publications

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“…In this study, investigated Thirty-four molecules that passed the ADMET screening were for further molecular docking. These selected molecules along with native ligands, and reference drugs, were evaluated against NS5 methyl transferase (chain A), where competitive inhibition was observed between proteins and flavonoids, consistent with recent research [61]. Among the 34 flavonoids studied, binding affinities ranging from −10.2 to −7.6 kcal/mol, surpassing those of the reference ligand (−7.6 kcal/mol) and reference drug (−7.3 kcal/mol) (Table 1), indicating higher binding efficiency and stability of the complexes [62].…”

Section: Resultssupporting

confidence: 80%

“…A spike at 130 ns of RMSD of protein backbone might be the reason for a bump of RMSD of ligand around the same region of the trajectory. The ligands were stable in the SAM binding pocket during MDS which is also the same as that reported in the previous study [61]. Fig 10 shows snapshots taken at different moments to illustrate how a molecular-level understanding may be attained in terms of the geometry and dynamics of the atoms…”

Section: Resultssupporting

confidence: 73%

Section: Root Mean Square Deviation (Rmsd)supporting

confidence: 87%

“…In this study, investigated Thirty-four molecules that passed the ADMET screening were for further molecular docking. These selected molecules along with native ligands, and reference drugs, were evaluated against NS5 methyl transferase (chain A), where competitive inhibition was observed between proteins and flavonoids, consistent with recent research [61]. Among the were engaged with all the protein-ligand complexes, which is the same as in previous studies with (same receptor) the distinction being a variation in residue number [63,64].…”

Section: Molecular Docking Analysissupporting

confidence: 76%

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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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Section: Resultssupporting

confidence: 80%

Section: Resultssupporting

confidence: 73%

Section: Root Mean Square Deviation (Rmsd)supporting

confidence: 87%

“…In this study, investigated Thirty-four molecules that passed the ADMET screening were for further molecular docking. These selected molecules along with native ligands, and reference drugs, were evaluated against NS5 methyl transferase (chain A), where competitive inhibition was observed between proteins and flavonoids, consistent with recent research [61]. Among the were engaged with all the protein-ligand complexes, which is the same as in previous studies with (same receptor) the distinction being a variation in residue number [63,64].…”

Section: Molecular Docking Analysissupporting

confidence: 76%

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In silico exploration of potent flavonoids for dengue therapeutics

Phunyal,

Adhikari Subin,

Adhikari

2024

Preprint

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“…[45] At the concentration of 30 μM, the compound 3 q, 3 h and 3 m showed 87, 83 and 91 % cell viability in this assay indicating the lack of their significant cytotoxic effects toward these cells. Next, in a preliminary in vitro assay, [46] Vero cells were infected with DENV2 at multiplicity of infection (MOI) 0.2, and then treated with 10 μM of compound 3 q or with 0.1 %DMSO (virus control). The determination of protein level of DENV2 virus at 48 h post infection indicated 56.2 � 4.3 % inhibition (experiments were carried out independently in triplicate) thereby potential of 3 q against DENV2.…”

Section: Resultsmentioning

confidence: 99%

In Silico Evaluation of 1‐Aminoisoquinoline Derivatives against Dengue Virus: Greener Access via a Sonochemical Method

Prasada Rao,

Bhuvan Tej,

Raju

et al. 2024

ChemistrySelect

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The reported antiviral properties of isoquinolines including that of berberine against dengue virus prompted us exploring a series of 1‐aminoisoquinoline derivatives against RdRp and MTase domain of NS5 protein of dengue virus (DENV) in silico. While MTase is known to assists in viral RNA capping, the RdRp plays a key role in the virus replication. The docking of 1‐aminoisoquinolines into the DENV NS5 protein RdRp domain (PDB: 5I3Q) in silico revealed good interactions of one molecule involving the H‐bond interactions through its NO2 group with GLN802, LEU511 and HIS512 residues. Notably, the docking of these compounds into the DENV NS5 protein DENV3 MTase (PDB: 5EHG) in silico also indicated same molecule as the most encouraging potential entity as the molecule participated in three H‐bond interactions through its NO2 group with GLY86, TRP87, SER56 residues. The synthesis of 1‐aminoisoquinolines was undertaken under sonochemical conditions via the reaction of 1‐chloroisoquinoline with appropriate amines in the presence of Cs2CO3 in DMSO. Among them, three encouraging compounds did not cause any significant cytotoxicity towards Vero cells but showed good to moderate inhibition of DENV2.

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Viral RNA capping: Mechanisms and antiviral therapy

Chen,

Jiang,

et al. 2024

Journal of Medical Virology

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RNA capping is an essential trigger for protein translation in eukaryotic cells. Many viruses have evolved various strategies for initiating the translation of viral genes and generating progeny virions in infected cells via synthesizing cap structure or stealing the RNA cap from nascent host messenger ribonucleotide acid (mRNA). In addition to protein translation, a new understanding of the role of the RNA cap in antiviral innate immunity has advanced the field of mRNA synthesis in vitro and therapeutic applications. Recent studies on these viral RNA capping systems have revealed startlingly diverse ways and molecular machinery. A comprehensive understanding of how viruses accomplish the RNA capping in infected cells is pivotal for designing effective broad‐spectrum antiviral therapies. Here we systematically review the contemporary insights into the RNA‐capping mechanisms employed by viruses causing human and animal infectious diseases, while also highlighting its impact on host antiviral innate immune response. The therapeutic applications of targeting RNA capping against viral infections and the development of RNA‐capping inhibitors are also summarized.

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In silico and in vitro studies of potential inhibitors against Dengue viral protein NS5 Methyl Transferase from Ginseng and Notoginseng

Cited by 10 publications

References 61 publications

In silico exploration of potent flavonoids for dengue therapeutics

In silico exploration of potent flavonoids for dengue therapeutics

In Silico Evaluation of 1‐Aminoisoquinoline Derivatives against Dengue Virus: Greener Access via a Sonochemical Method

Viral RNA capping: Mechanisms and antiviral therapy

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