Biological Evaluation, Chelation, and Molecular Modeling Studies of Novel Metal-Chelating Inhibitors of NF-κB-DNA Binding:  Structure Activity Relationships

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

doi:10.1021/jm050617x

Cited by 18 publications

(16 citation statements)

References 35 publications

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“…So, we suggest that site 1 may be the real active site and these kinds of compounds are NF-kB-DNA binding inhibitors, which prevent free NF-kB from binding to DNA. These conclusions were consistent with the results of Sharma et al [8].…”

Section: Comsia Model and Binding Sitesupporting

confidence: 94%

“…In order to have an electrostatic complementarity with the DBR, it is necessary that the designed inhibitors should have a negative potential around them. One red-colored contour (4) lays on the phenyl and two red-colored contours (7,8) appear below substituent X (see Figure 13A). Compounds 14, 15, and 19 -29 have an oxygen atom in first atom of substituent X; this O atom can bring more negative charge to this region.…”

Section: Comfa Model and Binding Sitementioning

confidence: 99%

“…In Figure 10C, the positions of two blue-colored contours are shown just located on the blue (SER 208) and red (GLU 22, PHE 17) areas of p50. Currently, the drugs studied against NF-kB fall mainly into three categories: (1) antioxidants against oxidative stress conditions which aid in NF-kB activation; (2) NF-kB phosphorylation and degradation inhibitors (IKK and proteasome inhibitors); (3) NF-kB-DNA binding inhibitors [8]. From the present study, we find that the results of 3D-QSAR were in good agreement with the structural characteristics of the corresponding binding site (site 1).…”

Section: Comsia Model and Binding Sitementioning

confidence: 99%

“…For example, this free NF-kB can bind to its target sites (kB sites in the DNA) to initiate transcription. These kB sites are also present in the Long Terminal Repeat (LTR) of HIV-1, and hence NF-kB (p50 subunit) binding to LTR-DNA is critical in viral replication [6,8,19].…”

Section: Introductionmentioning

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%

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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: Comsia Model and Binding Sitesupporting

confidence: 94%

Section: Comfa Model and Binding Sitementioning

confidence: 99%

Section: Comsia Model and Binding Sitementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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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Regulatory Fe^II/III Heme: The Reconstruction of a Molecule's Biography

Kühl

Imhof

2014

ChemBioChem

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More than 20 years of research on heme as a temporary effector molecule of proteins have revealed its widespread impact on virtually all primary functions in the human organism. As our understanding of this influence is still growing, a comprehensive overview of compiled data will give fresh impetus for creativity and developing new strategies in heme-related research. From known data concerning heme-regulated proteins and their involvement in the development of diseases, we provide concise information of Fe(II/III) heme as a regulator and the availability of "regulatory heme". The latter is dependent on the balance between free and bound Fe(II/III) heme, here termed "hemeostasis". Imbalance of this system can lead to the development of diseases that were not always attributed to this small molecule. Diseases such as cancer or Alzheimer's disease highlight the reawakened interest in heme, whose function was previously believed to be completely understood.

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Virtual Screening against p50 NF‐κB Transcription Factor for the Identification of Inhibitors of the NF‐κB–DNA Interaction and Expression of NF‐κB Upregulated Genes

Piccagli¹,

Fabbri²,

Borgatti³

et al. 2009

ChemMedChem

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Virtual screening against NF-kappaB p50 using docking simulations was applied by starting from a three-dimensional (3D) database containing more than 4.6 million commercially available structures. This database was filtered by specifying a subset of commercially available compounds sharing a (2E,Z)-3-(2-hydroxyphenyl)-2-propenoate substructure and relevant druglike properties. Docking to p50 NF-kappaB was performed with a test set of six known inhibitors of NF-kappaB-DNA interactions. In agreement with docking results, the highest-scored compound displayed a high level of inhibitory activity in electrophoretic mobility shift assay (EMSA) experiments (inhibition of NF-kappaB-DNA interactions) and on biological functions dependent on NF-kappaB activity (inhibition of IL-8 gene expression in cystic fibrosis IB3-1 cells). We found that this in silico screening approach is suitable for the identification of low-molecular-weight compounds that inhibit NF-kappaB-DNA interactions and NF-kappaB-dependent functions. Information deduced from the discovery of the new lead compound and its binding mode could result in further lead optimization resulting in more potent NF-kappaB inhibitors.

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Biological Evaluation, Chelation, and Molecular Modeling Studies of Novel Metal-Chelating Inhibitors of NF-κB-DNA Binding: Structure Activity Relationships

Cited by 18 publications

References 35 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

Regulatory Fe^II/III Heme: The Reconstruction of a Molecule's Biography

Virtual Screening against p50 NF‐κB Transcription Factor for the Identification of Inhibitors of the NF‐κB–DNA Interaction and Expression of NF‐κB Upregulated Genes

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Biological Evaluation, Chelation, and Molecular Modeling Studies of Novel Metal-Chelating Inhibitors of NF-κB-DNA Binding: Structure Activity Relationships

Cited by 18 publications

References 35 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

Regulatory FeII/III Heme: The Reconstruction of a Molecule's Biography

Virtual Screening against p50 NF‐κB Transcription Factor for the Identification of Inhibitors of the NF‐κB–DNA Interaction and Expression of NF‐κB Upregulated Genes

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Product

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Regulatory Fe^II/III Heme: The Reconstruction of a Molecule's Biography