Skeleton selectivity in complexation of chelerythrine and chelerythrine-like natural plant alkaloids with the G-quadruplex formed at the promoter of c-MYC oncogene: in silico exploration

Bhat, Jyotsna; Chatterjee, Subhrangsu

doi:10.1039/c6ra04671a

Cited by 8 publications

(17 citation statements)

References 73 publications

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“…As seen in Table S1 , the selected ligand molecules, through virtual screening and molecular docking, fulfill the criteria for druglikeness. All possess a negative docking score (better than chelerythrine 43 ), and respective docked conformations are shown in Figure S1 . TPP forms polar interactions with A15 and CH−π interactions with A6 and G14.…”

Section: Resultsmentioning

confidence: 99%

“…The initial model structure of the G-quadruplex formed in Pu27 was kept the same as that reported in the previous study. 43 It was built over the template of the NMR solution structure (PDB-ID 2A5P) 25 using Maestro 45 and further details are as documented previously. 43 On the basis of the information provided in the literature, 23 , 25 , 28 , 43 the 5′ end of Pu27 was taken as the ligand binding site.…”

Section: Methodsmentioning

confidence: 99%

“… 42 In our previous study, we followed the in silico approach for screening the natural drug database with chelerythrine-like molecules and determined the pharmacophoric features essential for stabilizing the quadruplex formed in Pu27 . 43 …”

Section: Introductionmentioning

confidence: 99%

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In Silico Screening and Binding Characterization of Small Molecules toward a G-Quadruplex Structure Formed in the Promoter Region of c-MYC Oncogene

et al. 2017

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Overexpression of c-MYC oncogene is associated with cancer pathology. Expression of c-MYC is regulated by the G-quadruplex structure formed in the G-rich segment of nuclease hypersensitive element (NHE III1), that is, “Pu27”, which is localized in the promoter region. Ligand-induced stabilization of the Pu27 structure has been identified as a novel target for cancer therapeutics. Here, we have explored the library of synthetic compounds against the predefined binding site of Pu27. Three compounds were selected based on the docking analyses; they were further scrutinized using all atom molecular dynamics simulations in an explicit water model. Simulated trajectories were scrutinized for conformational stability and ligand binding free energy estimation; essential dynamic behavior was determined using principal component analysis. One of the molecules, “TPP (1-(3-(4-(1,2,3-thiadiazol-4-yl)phenoxy)-2-hydroxypropyl)-4-carbamoylpiperidinium)”, with the best results was considered for further evaluation. The theoretical observations are supported well by biophysical analysis using circular dichroism, isothermal titration calorimetry, and high-resolution NMR spectroscopy indicating association of TPP with Pu27. The in vitro studies were then translated into c-MYC overexpression in the T47D breast cancer cell line. Biological evaluation through the MTT assay, flow cytometric assay, RT-PCR, and reporter luciferase assay suggests that TPP downregulates the expression of c-MYC oncogene by arresting its promoter region. In silico and in vitro observations cumulatively suggest that the novel skeleton of TPP could be a potential anticancer agent by stabilizing the G-quadruplex formed in the Pu27 and consequently downregulating the expression of c-MYC oncogene. Derivation of new molecules on its skeleton may confer anticancer therapeutics for the next generation.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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In Silico Screening and Binding Characterization of Small Molecules toward a G-Quadruplex Structure Formed in the Promoter Region of c-MYC Oncogene

et al. 2017

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“…We determined conformational maintenance and distinctions on the basis of the root‐mean‐square deviation (RMSD) values. A high RMSD value indicates a flexible nature of the protein, which causes overall instability of the protein's secondary structure . Cpptraj script were incorporated to calculate the RMSD values .…”

Section: Resultsmentioning

confidence: 99%

A Small Molecule Impedes Insulin Fibrillation: Another New Role of Phenothiazine Derivatives

2017

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Protein misfolding is interrelated to several diseases, including neurodegenerative diseases and type II diabetes. Misfolded/unfolded proteins produce soluble oligomers that accumulate into “amyloid plaques”. Inhibition of amyloid‐plaque formation by those misfolded/unfolded proteins will lead to the invention of new therapeutic approaches for amyloid‐related diseases. Herein, methylene blue (MB), a well‐defined drug against multiple diseases and disorders, is used to impede insulin fibrillation. In this study, we perform an array of in vitro experiments to monitor the effects of MB on the fibrillation of bovine insulin. Our results confirm that MB distresses the kinetics of insulin fibrillation by interacting with insulin in its monomeric form. A thioflavin T assay indicates that insulin fibrillation is interrupted upon the addition of MB. The same results are confirmed by circular dichroism, dynamic light scattering (DLS), and size‐exclusion chromatography (SEC). According to the DLS data, the insulin fibrils are 800 nm in diameter, and the addition of MB reduces the size of the fibrils, which remain 23 nm in size, and this indicates that no fibrillation of insulin occurs in the presence of MB. This data is also supported by SEC. Saturation transfer difference NMR spectroscopy and molecular dynamics simulations demonstrate the interactions between insulin and MB at the atomic level.

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“…Standard simulation protocol was followed as per our previous studies [ 49 ]. Quadruplex system was parameterized with FF14SB [ 50 – 53 ], other fragments were parameterized with GAFF [ 52 ].…”

Section: Methodsmentioning

confidence: 99%

LINCRNA00273 promotes cancer metastasis and its G-Quadruplex promoter can serve as a novel target to inhibit cancer invasiveness

Jana

Patra

et al. 2017

Oncotarget

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Discovery of anti-metastatic drugs is of immense clinical significance as metastasis is responsible for 90% of all cancer deaths. Here we report the inhibitory effect of a bis schiff base (M2) on cancer cell migration and invasion in vitro and in vivo. M2 has shown good solubility and permeability across the intestinal cell wall and hence can be classified as BCS (Biopharmaceutical classification system) class I. Microarray studies identified a long non coding intergenic RNA, LINC00273 as a novel molecular target of M2. We report that LINC00273 harbors a unique (4n-1) parallel G-Quadruplex structure in its promoter as validated by DMS footprint. M2 is proposed to stabilize this G-quadruplex structure resulting in the down-regulation of LINC00273 expression. Dual Luciferase reporter assay also suggests inhibition of LINC00273 promoter activity by M2. Involvement of this linc in metastasis is proven by siRNA and shRNA mediated knock down of LINC00273 in vitro and in vivo in nude mice which significantly decelerates cancer cell migration and invasion and also makes the cells unresponsive to TGF-β's pro-metastatic effects. Furthermore, the real time expression of LINC00273 in thirty seven human clinical samples is found to be positively correlated with the histopathological staging of metastasis.

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Skeleton selectivity in complexation of chelerythrine and chelerythrine-like natural plant alkaloids with the G-quadruplex formed at the promoter of c-MYC oncogene: in silico exploration

Abstract: Chelerythrine binds at the 5′ end and arrests the G-quadruplex formed in the promoter region ofc-MYConcogene thus restrict thec-MYCexpression. Position of methoxy group over the core skeleton of chelerythrine determines the binding pattern of ligand.

Cited by 8 publications

References 73 publications

In Silico Screening and Binding Characterization of Small Molecules toward a G-Quadruplex Structure Formed in the Promoter Region of c-MYC Oncogene

In Silico Screening and Binding Characterization of Small Molecules toward a G-Quadruplex Structure Formed in the Promoter Region of c-MYC Oncogene

A Small Molecule Impedes Insulin Fibrillation: Another New Role of Phenothiazine Derivatives

LINCRNA00273 promotes cancer metastasis and its G-Quadruplex promoter can serve as a novel target to inhibit cancer invasiveness

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