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Polyphenol Compound as a Transcription Factor Inhibitor.

Park S - Nutrients (2015)

Bottom Line: Although their mechanism of action is not fully defined, polyphenols including flavonoids were found to act mostly as site-directed small molecule inhibitors on signaling.There are many reports in the literature of screening initiatives suggesting improved drugs that can modulate the transcription factor interactions responsible for disease.In this review, we focus on polyphenol compound inhibitors against dimeric forms of transcription factor components of intracellular signaling pathways (for instance, c-jun/c-fos (Activator Protein-1; AP-1), c-myc/max, Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and β-catenin/T cell factor (Tcf)).

View Article: PubMed Central - PubMed

Affiliation: Department of Applied Chemistry, Dongduk Women's University, Seoul 136-714, Korea. sypark21@dongduk.ac.kr.

ABSTRACT
A target-based approach has been used to develop novel drugs in many therapeutic fields. In the final stage of intracellular signaling, transcription factor-DNA interactions are central to most biological processes and therefore represent a large and important class of targets for human therapeutics. Thus, we focused on the idea that the disruption of protein dimers and cognate DNA complexes could impair the transcriptional activation and cell transformation regulated by these proteins. Historically, natural products have been regarded as providing the primary leading compounds capable of modulating protein-protein or protein-DNA interactions. Although their mechanism of action is not fully defined, polyphenols including flavonoids were found to act mostly as site-directed small molecule inhibitors on signaling. There are many reports in the literature of screening initiatives suggesting improved drugs that can modulate the transcription factor interactions responsible for disease. In this review, we focus on polyphenol compound inhibitors against dimeric forms of transcription factor components of intracellular signaling pathways (for instance, c-jun/c-fos (Activator Protein-1; AP-1), c-myc/max, Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and β-catenin/T cell factor (Tcf)).

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The lowest energy conformation of curcumin and DHGA.
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nutrients-07-05445-f001: The lowest energy conformation of curcumin and DHGA.

Mentions: The low energy conformations of curcumin and DHGA inhibitors have “V-shaped” two-fold symmetry as shown in Figure 1 [49]. Conformational studies of these inhibitors revealed that they share a common conformational feature. The two-fold symmetry of molecular conformation is also a characteristic of fos-jun or myc-max transcription activators that function as dimer proteins. As a result, a stable binding mode was proposed due to two potential interactions between the protein and the inhibitor. One is a hydrogen bond and/or an electrostatic interaction between the acidic hydroxyl (OH)-group in the phenol ring of the inhibitor and the amino-group of the basic amino acid, which is abundant in the DNA binding region of the dimeric forms of the transcription factor. The other is a hydrophobic interaction between the hydrocarbon chain of the inhibitor and the hydrocarbon chain of the amino acid in the fos-jun protein [49]. The inhibitors have differences in their molecular structures. DHGA and NDGA have the same hydrophobic carbon chain. DHGA has one phenolic OH and one methoxy group on each side while NDGA has two phenolic OH groups on each side. The methoxy group of DHGA cannot form hydrogen bonds. This might make DHGA a less potent inhibitor than NDGA. Although curcumin has one phenolic OH on each side, the conjugated double bond of the hydrophobic carbon chain may cause curcumin to be more hydrophobic than the other two inhibitors. It was also suggested that the rigid conformation of curcumin provides a better acidic OH and hydrocarbon orientation for interactions with the fos-jun protein [49]. Actually, the lowest interaction energy for each inhibitor, which was obtained using Monte Carlo docking simulations, showed a correlation with the IC50 value of each inhibitor, which was experimentally determined.


Polyphenol Compound as a Transcription Factor Inhibitor.

Park S - Nutrients (2015)

The lowest energy conformation of curcumin and DHGA.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663573&req=5

nutrients-07-05445-f001: The lowest energy conformation of curcumin and DHGA.
Mentions: The low energy conformations of curcumin and DHGA inhibitors have “V-shaped” two-fold symmetry as shown in Figure 1 [49]. Conformational studies of these inhibitors revealed that they share a common conformational feature. The two-fold symmetry of molecular conformation is also a characteristic of fos-jun or myc-max transcription activators that function as dimer proteins. As a result, a stable binding mode was proposed due to two potential interactions between the protein and the inhibitor. One is a hydrogen bond and/or an electrostatic interaction between the acidic hydroxyl (OH)-group in the phenol ring of the inhibitor and the amino-group of the basic amino acid, which is abundant in the DNA binding region of the dimeric forms of the transcription factor. The other is a hydrophobic interaction between the hydrocarbon chain of the inhibitor and the hydrocarbon chain of the amino acid in the fos-jun protein [49]. The inhibitors have differences in their molecular structures. DHGA and NDGA have the same hydrophobic carbon chain. DHGA has one phenolic OH and one methoxy group on each side while NDGA has two phenolic OH groups on each side. The methoxy group of DHGA cannot form hydrogen bonds. This might make DHGA a less potent inhibitor than NDGA. Although curcumin has one phenolic OH on each side, the conjugated double bond of the hydrophobic carbon chain may cause curcumin to be more hydrophobic than the other two inhibitors. It was also suggested that the rigid conformation of curcumin provides a better acidic OH and hydrocarbon orientation for interactions with the fos-jun protein [49]. Actually, the lowest interaction energy for each inhibitor, which was obtained using Monte Carlo docking simulations, showed a correlation with the IC50 value of each inhibitor, which was experimentally determined.

Bottom Line: Although their mechanism of action is not fully defined, polyphenols including flavonoids were found to act mostly as site-directed small molecule inhibitors on signaling.There are many reports in the literature of screening initiatives suggesting improved drugs that can modulate the transcription factor interactions responsible for disease.In this review, we focus on polyphenol compound inhibitors against dimeric forms of transcription factor components of intracellular signaling pathways (for instance, c-jun/c-fos (Activator Protein-1; AP-1), c-myc/max, Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and β-catenin/T cell factor (Tcf)).

View Article: PubMed Central - PubMed

Affiliation: Department of Applied Chemistry, Dongduk Women's University, Seoul 136-714, Korea. sypark21@dongduk.ac.kr.

ABSTRACT
A target-based approach has been used to develop novel drugs in many therapeutic fields. In the final stage of intracellular signaling, transcription factor-DNA interactions are central to most biological processes and therefore represent a large and important class of targets for human therapeutics. Thus, we focused on the idea that the disruption of protein dimers and cognate DNA complexes could impair the transcriptional activation and cell transformation regulated by these proteins. Historically, natural products have been regarded as providing the primary leading compounds capable of modulating protein-protein or protein-DNA interactions. Although their mechanism of action is not fully defined, polyphenols including flavonoids were found to act mostly as site-directed small molecule inhibitors on signaling. There are many reports in the literature of screening initiatives suggesting improved drugs that can modulate the transcription factor interactions responsible for disease. In this review, we focus on polyphenol compound inhibitors against dimeric forms of transcription factor components of intracellular signaling pathways (for instance, c-jun/c-fos (Activator Protein-1; AP-1), c-myc/max, Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and β-catenin/T cell factor (Tcf)).

Show MeSH
Related in: MedlinePlus