Targeting FGL2, a Molecular Drug Target for Glioblastoma, With Natural Compounds Through Virtual Screening Method

Shah, Fahad Hassan; Kim, Song Ja

doi:10.4155/fmc-2020-0331

Cited by 4 publications

(6 citation statements)

References 50 publications

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“…Both compounds exploited terminal hydroxyl groups to establish hydrogen bonds, whereas benzene rings formed hydrophobic pianionic bonds. The intermolecular interaction energy was adequate and the RMSD comparison with benzarone was ≈ 2.24-2.63 Å, within the range of stability (Shah et al, 2020(Shah et al, , 2021.…”

Section: Discussionmentioning

confidence: 85%

“…Results showed that 1,7-dihydroxy-3-methylanthracene-9.10-dione had the RMSD of 2.24 Å, and 2.63 Å for Sorbifolin, which are adequately stable values (Shah et al, 2020(Shah et al, , 2021.…”

Section: Virtual Screening Resultsmentioning

confidence: 97%

“…The Swiss-model database built the 3D-structure of the EYA3 protein, which was then refined and minimized with GalaxyRefine database (Heo et al, 2013). After refinement, the structural and topological features of the EYA3 protein template was determined using protein model validation database such as ERRAT, Verify 3D, ProCHECK, Pro-SA, VADAR and ResPROX (Shah et al, 2021).…”

Section: Construction and Validation Of Protein Modelmentioning

confidence: 99%

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Inhibitors of EYA3 Protein in Ewing Sarcoma

Shah

Kim

2022

Asian Pac J Cancer Prev

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Objective: Among sarcomas, Ewing sarcoma (EWS) is characterized as a highly malignant type of bone tumor caused by the fusion of EWS RNA Binding Protein-1 (EWSR1)/ Friend leukemia integration 1 (FLI1) genes. The product of fusion gene gives rise to EWSR1/FLI1 which activates the activity of Eyes absent homolog 3 (EYA3) which causes tumor growth and angiogenesis. EYA3 is now considered as a therapeutic drug target for EWS . The study was designed to gather potential inhibitors for the EYA3 target using medicinal compounds. Methods: In this study, we have obtained a list of medicinal compounds from the NuBBE database and downloaded their structural information. Then insilico screening analysis of >2,000 medicinal compounds was performed with PyRX virtual drug screening software to discover potential inhibitors for the treatment of EWS. Results: Our investigation revealed that Sorbifolin and 1,7-Dihydroxy-3-methylanthracene-9.10-dione show interactive affinity for EYA3 active residues. Moreover, these compounds have adequate toxicity, can induce cytotoxicity in EWS cells, and are capable of regulating the expression of genes activated by EWSR1/FLI1. Conclusion: Our study concluded that Sorbifolin and 1,7-Dihydroxy-3-methylanthracene-9.10-dione are promising drug candidates for the treatment of EWS and should be further subjected to invitro testing.

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Section: Discussionmentioning

confidence: 85%

Section: Virtual Screening Resultsmentioning

confidence: 97%

Section: Construction and Validation Of Protein Modelmentioning

confidence: 99%

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Inhibitors of EYA3 Protein in Ewing Sarcoma

Shah

Kim

2022

Asian Pac J Cancer Prev

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“…Our virtual screening analysis showed that cordycepin and geraniol are promising ligands as they established hydrogen bonds with the reported active site residues of these receptors. Hydrogen bonding of compounds brings disturbance in the structure and function of protein target which ultimately leads to their inhibition as evident from these studies [16,[42][43][44][45] . Moreover, we also determined the toxic side effects and lethal dose of these compounds to ensure safety and dose calibration during in vitro experimentations to procure maximal affectivity against OA.…”

Section: Resultsmentioning

confidence: 97%

“…The interaction of ligands with considered receptors was determined by PYRX 0.9 software [16] . The ligands were aimed at the reported active site residues of these receptors for interaction to obtain potential inhibitors to disturb the degenerative pathway governed by these proteins.…”

Section: Virtual Screening and Docking Validationmentioning

confidence: 99%

Finding Natural Compounds as Potential Inhibitors for Osteoarthritis

Shah¹,

Eom²,

Ko³

et al. 2022

IJPS

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Shah et al.: Natural Compounds for OsteoarthritisOsteoarthritis is the fourth leading cause of disability affecting more than 300 million people around the globe. In this disease, chondrocytes responsible for the growth and maintenance of articular joints start to deplete due to the rogue involvement of phosphoinositide 3-kinase, protein kinase-B and p38 mitogenactivated protein kinases. Presently, there are medications providing symptomatic treatment, however, they cannot thwart the progression of osteoarthritis. Natural compounds can rejuvenate injured tissues, averting inflammation and can be useful for treating osteoarthritis. The present study was conducted to obtain inhibitors using natural compounds for phosphoinositide 3-kinase/protein kinase-B/mitogenactivated protein kinases implicated in the pathogenesis of osteoarthritis. Results revealed that out of 1541 natural compounds, cordycepin and geraniol formed an inhibitory interaction with these kinases. Moreover, these compounds down regulated important inflammatory markers (DNA methyltransferase 1, cluster of differentiation 74 and ETS proto-oncogene 1) and increased the expression of glutamate-cysteine ligase catalytic, FAM111 trypsin like peptidase A, secreted frizzled related protein 1 and ferritin light chain genes implicated in the survival of chondrocytes. The absorption, distribution, metabolism, excretion, toxicity and lethal dose prediction studies showed that cordycepin has appropriate pharmacokinetics and low acute toxicity level, whereas geraniol has high toxicity level and efficient pharmacokinetic profile. Our study provided a preliminary insight that cordycepin and geraniol are capable inhibitors of phosphoinositide 3-kinase/protein kinase-B/mitogen-activated protein kinases and can be lead compounds in osteoarthritis therapy.

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sFgl2 gene-modified MSCs regulate the differentiation of CD4+ T cells in the treatment of autoimmune hepatitis

Ji,

Wang,

et al. 2023

Stem Cell Res Ther

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Background Autoimmune hepatitis (AIH) is a T-cell-mediated autoimmune liver disease that can lead to liver injury and has a poor long-term prognosis. Mesenchymal stromal cells (MSCs) have immunosuppressive effects and can treat AIH. CD4+ T cells express the unique inhibitory Fcγ receptor (FcγRIIB), which is the only receptor for the immunosuppressive factor soluble fibrinogen-like protein 2 (sFgl2). This study aimed to examine the therapeutic effect of sFgl2 gene-modified MSCs (sFgl2-MSCs) on AIH. Methods MSCs were obtained from the inguinal fat of mice and cocultured with CD4+ T cells sorted from mouse spleens. FcγRIIB expression on CD4+ T cells was determined by flow cytometry. sFgl2 expression in MSCs transfected with lentiviral vectors carrying the Fgl2 gene and a green fluorescent protein-encoding sequence was determined by enzyme-linked immunosorbent assay. The percentages of Th1 cells Th17 cells and regulatory T cells (Tregs) were determined by flow cytometry And the levels of p-SHP2 and p-SMAD2/3 were detected by Western blotting after the cells were cocultured with MSCs for 72 h. After locating MSCs by in vivo imaging Con A-induced experimental AIH mice were randomly divided into 4 groups and administered different treatments. After 24 h histopathological scores liver function and cytokine levels were examined and the proportions of CD4+ T cells CD8+ T cells Tregs Th17 cells and Th1 cells in the spleen and liver were determined by flow cytometry. In addition immunohistochemical staining was used to detect the liver infiltration of T-bet-, Foxp3- and RORγ-positive cells. Results FcγRIIB expression on CD4+ T cells was upregulated after coculture with MSCs. After coculture with sFgl2-MSCs, the proportion of Tregs among CD4+ T cells increased, the proportion of Th17 and Th1 cells decreased, and the levels of p-SHP2 and p-SMAD2/3 increased. In vivo, sFgl2-MSCs significantly improved liver function, decreased liver necrosis area, decreased tumor necrosis factor-α, interleukin (IL)-1β and IL-6 expression, increased IL-10 expression, reduced liver infiltration of CD4+ T and CD8+ T cells, increased the proportion of Tregs and reduced the proportions of Th17 and Th1 cells in mice. Conclusion By promoting Tregs differentiation and inhibiting Th17 and Th1 cell differentiation, sFgl2 gene-modified MSCs have a more powerful therapeutic effect on Con A-induced experimental AIH and may represent a strategy for the clinical treatment of AIH.

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Targeting FGL2, a Molecular Drug Target for Glioblastoma, With Natural Compounds Through Virtual Screening Method

Cited by 4 publications

References 50 publications

Inhibitors of EYA3 Protein in Ewing Sarcoma

Inhibitors of EYA3 Protein in Ewing Sarcoma

Finding Natural Compounds as Potential Inhibitors for Osteoarthritis

sFgl2 gene-modified MSCs regulate the differentiation of CD4+ T cells in the treatment of autoimmune hepatitis

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