Inhibitory activity of polyhydroxycarboxylate chelators against recombinant NF-κB p50 protein–DNA binding

Sharma, Rakesh Kumar; Pande, Vineet; Ramos, María J.; Chopra, Sonia; Meguro, Kazuyuki; Inoue, Jun; Otsuka, Masami

doi:10.1016/j.bioorg.2004.12.001

Cited by 10 publications

(13 citation statements)

References 21 publications

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“…Internal validation using Leave-OneOut (LOO) cross-validation gave a correlation coefficient q 2 LOO of 0.822 and a Standard Error of Prediction (SDE-PLOO) of 0.126. Moreover, the optimum number of components is 4, r 2 is 0.985, and F (4,25) is 243.915 for noncrossvalidation. The CoMFA results are summarized in Table 2.…”

Section: Comfa Analysismentioning

confidence: 99%

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3D‐QSAR and Docking Studies of Quinazoline Derivatives with the Inhibitory Activity Toward NF‐κB

Shen

Chen

et al. 2008

QSAR Comb. Sci.

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Nuclear Factor-kB (NF-kB) is an important transcription factor for regulation expression of many cytokines that are involved in the pathogenesis of inflammatory diseases such as Adult Respiratory Distress Syndrome (ARDS), sepsis syndrome, and HIV. It is recently proposed that quinazoline derivatives are capable of inhibiting the activation of NF-kB. To study the inhibiting mechanism and obtain some helpful information for designing functional inhibitor against the protein, 3-D Quantitative Structure -Activity Relationship (3D-QSAR) studies such as Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) and docking analysis on 29 inhibitors, quinazoline derivatives, have been carried out. The CoMFA and CoMSIA models give a cross-validated coefficient q 2 of 0.822 and 0.801, respectively. The binding pockets around the DNA binding sites in p50 and p65 have been tested for docking. The docking results at site 1 of p50 show a significant correlation between the energy scores and the corresponding experimental values with the correlation coefficient R ¼ 0.817. The contour maps of 3D-QSAR model are shown in a good agreement with the structural characteristics of the corresponding binding site. These results indicate a NF-kB-DNA binding inhibiting mechanism for these compounds, which prevent free NF-kB from binding to DNA. Therefore, the final 3D-QSAR models and the information of the binding site would be useful in developing new quinazoline derivatives with favorable activity.

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Section: Comfa Analysismentioning

confidence: 99%

“…It is also a novel approach to design anti-HIV gene expression inhibitors, which do not have the problem of resistance unlike in other inhibitors because anti-HIV inhibitors target the direct p50. P50 is a normal part of the T-cell and is not subject to mutation [6,8,24,25].…”

Section: Introductionmentioning

confidence: 99%

3D‐QSAR and Docking Studies of Quinazoline Derivatives with the Inhibitory Activity Toward NF‐κB

Shen

Chen

et al. 2008

QSAR Comb. Sci.

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“…After 20 min of incubation at room temperature, electrophoresis was performed using 6% polyacrylamide DNA retardation gels (Invitrogen) and the mixture then transferred to a positively charged nylon membrane (Immobilon-NY+ ; Millipore). After UV cross-linking, the biotin end-labeled DNA was detected using a streptavidinhorseradish peroxidase conjugate and LightShift chemiluminescent substrate [25].…”

Section: Electrophoretic Mobility Shift Assays (Emsas)mentioning

confidence: 99%

Inhibitory Effect of Emodin on Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) Expression in Rat Hepatic Stellate Cells

et al. 2006

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Emodin inhibited expression of both transforming growth factor beta1 (TGFbeta1)- and phorbol ester (PMA)-induced tissue inhibitors of metalloproteinase-1 (TIMP-1) in an immortalized rat hepatic stellate cell line, HSC-T6, by Western blot and reverse transcription polymerase chain reaction. Reporter gene assays showed that emodin reduced both basal and PMA-induced activated protein-1 (AP-1) promoter activities. Electrophoretic mobility shift assay revealed that emodin reduced AP-1 DNA binding activities in HSC-T6 cells. AP-1 components analysis showed that emodin also attenuated JunD mRNA expression. Furthermore, emodin markedly inhibited TGFbeta1-induced p42/p44 mitogen-activated protein kinase phosphorylation but did not alter PMA induction. We conclude that emodin effectively inhibits PMA- and TGFbeta1-stimulated TIMP-1 expression in hepatic stellate cells by suppressing the AP-1 signaling pathway and extracellular signal-regulated kinase activation, respectively. These data provide new insight into the cellular and molecular mechanisms of emodin against liver fibrosis.

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“…Structurally different inhibitors of the NF-kappaB/DNA interactions with a rather low binding constant (in the range of 30 μM and 500 μM) are reported in the literature [ 5 - 7 ]. Recently, some molecular modelling studies have predicted possible binding mode of the inhibitors molecules to the DNA binding region of subunit p50, starting from the crystallographic structure of the NF-kappaB homodimer [ 6 - 9 ].…”

Section: Introductionmentioning

confidence: 99%

Docking of molecules identified in bioactive medicinal plants extracts into the p50 NF-kappaB transcription factor: correlation with inhibition of NF-kappaB/DNA interactions and inhibitory effects on IL-8 gene expression

et al. 2008

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BackgroundThe transcription factor NF-kappaB is a very interesting target molecule for the design on anti-tumor, anti-inflammatory and pro-apoptotic drugs. However, the application of the widely-used molecular docking computational method for the virtual screening of chemical libraries on NF-kappaB is not yet reported in literature. Docking studies on a dataset of 27 molecules from extracts of two different medicinal plants to NF-kappaB-p50 were performed with the purpose of developing a docking protocol fit for the target under study.ResultsWe enhanced the simple docking procedure by means of a sort of combined target- and ligand-based drug design approach. Advantages of this combination strategy, based on a similarity parameter for the identification of weak binding chemical entities, are illustrated in this work with the discovery of a new lead compound for NF-kappaB. Further biochemical analyses based on EMSA were performed and biological effects were tested on the compound exhibiting the best docking score. All experimental analysis were in fairly good agreement with molecular modeling findings.ConclusionThe results obtained sustain the concept that the docking performance is predictive of a biochemical activity. In this respect, this paper represents the first example of successfully individuation through molecular docking simulations of a promising lead compound for the inhibition of NF-kappaB-p50 biological activity and modulation of the expression of the NF-kB regulated IL8 gene.

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Inhibitory activity of polyhydroxycarboxylate chelators against recombinant NF-κB p50 protein–DNA binding

Cited by 10 publications

References 21 publications

3D‐QSAR and Docking Studies of Quinazoline Derivatives with the Inhibitory Activity Toward NF‐κB

3D‐QSAR and Docking Studies of Quinazoline Derivatives with the Inhibitory Activity Toward NF‐κB

Inhibitory Effect of Emodin on Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) Expression in Rat Hepatic Stellate Cells

Docking of molecules identified in bioactive medicinal plants extracts into the p50 NF-kappaB transcription factor: correlation with inhibition of NF-kappaB/DNA interactions and inhibitory effects on IL-8 gene expression

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