An in-silico investigation of potential natural polyphenols for the targeting of COVID main protease inhibitor

Aljarba, Nada H.; Hasnain, Md Saquib; Bin-Meferij, Mashael Mohammed; Alkahtani, Saad

doi:10.1016/j.jksus.2022.102214

Cited by 8 publications

(3 citation statements)

References 45 publications

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“…It has even been pointed out that the intrinsic flexibility of proteasomal receptors and the dynamics of their ubiquitin interactions are likely paramount to substrate processing . It is important to point out that despite the fluctuating behavior of the dynamics obtained, the simulation period used has been widely recommended in several studies with similar oscillating behaviors and with trajectories that tended to be defined or discriminated at 100 ns with protease-type enzymes − including systems associated with Clp and even smaller simulation periods. − In addition, it is important to note that the simulation conditions used at 100 ns over pore1 in the presence of the substrate reproduced the reported radius (6–8 Å) for the crystallographic structure considered in this study . On the other hand, it is highlighted that despite having used two different methods to measure the radius of the pore1, and that these yielded results with different magnitudes, both were able to reproduce (at 100 ns) the previously reported radius of the pore1, and with a similar trend between the trajectories of both methods.…”

Section: Resultsmentioning

confidence: 99%

Intrinsic Dynamics of the ClpXP Proteolytic Machine Using Elastic Network Models

et al. 2023

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ClpXP complex is an ATP-dependent mitochondrial matrix protease that binds, unfolds, translocates, and subsequently degrades specific protein substrates. Its mechanisms of operation are still being debated, and several have been proposed, including the sequential translocation of two residues (SC/2R), six residues (SC/6R), and even long-pass probabilistic models. Therefore, it has been suggested to employ biophysical–computational approaches that can determine the kinetics and thermodynamics of the translocation. In this sense, and based on the apparent inconsistency between structural and functional studies, we propose to apply biophysical approaches based on elastic network models (ENM) to study the intrinsic dynamics of the theoretically most probable hydrolysis mechanism. The proposed models ENM suggest that the ClpP region is decisive for the stabilization of the ClpXP complex, contributing to the flexibility of the residues adjacent to the pore, favoring the increase in pore size and, therefore, with the energy of interaction of its residues with a larger portion of the substrate. It is predicted that the complex may undergo a stable configurational change once assembled and that the deformability of the system once assembled is oriented, to increase the rigidity of the domains of each region (ClpP and ClpX) and to gain flexibility of the pore. Our predictions could suggest under the conditions of this study the mechanism of the interaction of the system, of which the substrate passes through the unfolding of the pore in parallel with a folding of the bottleneck. The variations in the distance calculated by molecular dynamics could allow the passage of a substrate with a size equivalent to ∼3 residues. The theoretical behavior of the pore and the stability and energy of binding to the substrate based on ENM models suggest that in this system, there are thermodynamic, structural, and configurational conditions that allow a possible translocation mechanism that is not strictly sequential.

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Section: Resultsmentioning

confidence: 99%

Intrinsic Dynamics of the ClpXP Proteolytic Machine Using Elastic Network Models

et al. 2023

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“…Aljarba et al, using in silico ADME-tox prediction studies, suggest that Galangin has good absorption properties orally with good tolerance. Moreover, they posit that Galangin can be distributed throughout the body intactly to exhibit desired effect [ 34 ]. However, further investigations are warranted to explore the potential use of Galangin as a preventative measure.…”

Section: Discussionmentioning

confidence: 99%

In Silico Target Identification of Galangin, as an Herbal Flavonoid against Cholangiocarcinoma

et al. 2022

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Cholangiocarcinoma (CCA) is a heterogenous group of malignancies in the bile duct, which proliferates aggressively. CCA is highly prevalent in Northeastern Thailand wherein it is associated with liver fluke infection, or Opisthorchis viverrini (OV). Most patients are diagnosed in advanced stages, when the cancer has metastasized or severely progressed, thereby limiting treatment options. Several studies investigate the effect of traditional Thai medicinal plants that may be potential therapeutic options in combating CCA. Galangin is one such herbal flavonoid that has medicinal properties and exhibits anti-tumor properties in various cancers. In this study, we investigate the role of Galangin in inhibiting cell proliferation, invasion, and migration in OV-infected CCA cell lines. We discovered that Galangin reduced cell viability and colony formation by inducing apoptosis in CCA cell lines in a dose-dependent manner. Further, Galangin also effectively inhibited invasion and migration in OV-infected CCA cells by reduction of MMP2 and MMP9 enzymatic activity. Additionally, using proteomics, we identified proteins affected post-treatment with Galangin. Enrichment analysis revealed that several kinase pathways were affected by Galangin, and the signature corroborated with that of small molecule kinase inhibitors. Hence, we identified putative targets of Galangin using an in silico approach which highlighted c-Met as candidate target. Galangin effectively inhibited c-Met phosphorylation and subsequent signaling in in vitro CCA cells. In addition, Galangin was able to inhibit HGF, a mediator of c-Met signaling, by suppressing HGF-stimulated invasion, as well as migration and MMP9 activity. This shows that Galangin can be a useful anti-metastatic therapeutic strategy in a subtype of CCA patients.

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“…The RMSF was calculated from the MDS trajectory for the alpha carbon atom of the protein [70] and was found below 5 Å in most of the complexes indicating the stability of the complexes [71]. In the plot variations in the movement of individual amino acid residues compared to their unbound state.…”

Section: Root Mean Square Fluctuation (Rmsf)mentioning

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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An in-silico investigation of potential natural polyphenols for the targeting of COVID main protease inhibitor

Cited by 8 publications

References 45 publications

Intrinsic Dynamics of the ClpXP Proteolytic Machine Using Elastic Network Models

Intrinsic Dynamics of the ClpXP Proteolytic Machine Using Elastic Network Models

In Silico Target Identification of Galangin, as an Herbal Flavonoid against Cholangiocarcinoma

In silico exploration of potent flavonoids for dengue therapeutics

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