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Potential Protein Phosphatase 2A Agents from Traditional Chinese Medicine against Cancer.

Chen KC, Chen HY, Chen CY - Evid Based Complement Alternat Med (2014)

Bottom Line: As an environmental toxin, okadaic acid, is a tumor promoter and binds to PP2A catalytic C subunit and the cancer-associated mutations in PP2A structural A subunit in human tumor tissue; PP2A may have tumor-suppressing function.The results of docking simulation are optimized under dynamic conditions by MD simulations after virtual screening to validate the stability of H-bonds between PP2A- α protein and each ligand.Hence, we propose the TCM compounds, trichosanatine and squamosamide, as potential candidates as lead compounds for further study in drug development process with the PP2A- α protein.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, China Medical University, Taichung 40402, Taiwan.

ABSTRACT
Protein phosphatase 2A (PP2A) is an important phosphatase which regulates various cellular processes, such as protein synthesis, cell growth, cellular signaling, apoptosis, metabolism, and stress responses. It is a holoenzyme composed of the structural A and catalytic C subunits and a regulatory B subunit. As an environmental toxin, okadaic acid, is a tumor promoter and binds to PP2A catalytic C subunit and the cancer-associated mutations in PP2A structural A subunit in human tumor tissue; PP2A may have tumor-suppressing function. It is a potential drug target in the treatment of cancer. In this study, we screen the TCM compounds in TCM Database@Taiwan to investigate the potent lead compounds as PP2A agent. The results of docking simulation are optimized under dynamic conditions by MD simulations after virtual screening to validate the stability of H-bonds between PP2A- α protein and each ligand. The top TCM candidates, trichosanatine and squamosamide, have potential binding affinities and interactions with key residues Arg89 and Arg214 in the docking simulation. In addition, these interactions were stable under dynamic conditions. Hence, we propose the TCM compounds, trichosanatine and squamosamide, as potential candidates as lead compounds for further study in drug development process with the PP2A- α protein.

No MeSH data available.


Related in: MedlinePlus

Chemical scaffold of top four TCM candidates with their scoring function and sources.
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Related In: Results  -  Collection


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fig2: Chemical scaffold of top four TCM candidates with their scoring function and sources.

Mentions: For virtual screening, Dock Score energy function is used to rank the top potential TCM compounds; the chemical scaffold of top four TCM candidates with high binding affinity is displayed in Figure 2 with its scoring function and sources. The top four TCM compounds, trichosanatine, angeliferulate, dichotomoside E, and squamosamide, were extracted from Trichosanthes rosthornii Harms, Angelica sinensis, Stellaria dichotoma L., and Annona squamosa L., respectively. After the virtual screening, the docking poses of top four TCM compounds in the binding domain of PP2A-α are displayed in Figure 3. All the top four TCM compounds have interactions with key residues Arg89 and Arg214. Trichosanatine exists hydrogen bonds (H-bonds) with key residues Arg89 and Arg214. Angeliferulate has H-bonds with residues Arg89, Gln122, Arg214, and a π interaction with residue Trp200. Dichotomoside E forms H-bonds with residues Arg89, Tyr127, Gly215, and a π interaction with residue Arg214. Squamosamide has both H-bond and π interaction with residue Arg214. In addition, there exist H-bonds with residue Leu243 and a π interaction with residue Arg89. Those interactions hold the top four TCM compounds in the binding domain of PP2A-α protein.


Potential Protein Phosphatase 2A Agents from Traditional Chinese Medicine against Cancer.

Chen KC, Chen HY, Chen CY - Evid Based Complement Alternat Med (2014)

Chemical scaffold of top four TCM candidates with their scoring function and sources.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4020536&req=5

fig2: Chemical scaffold of top four TCM candidates with their scoring function and sources.
Mentions: For virtual screening, Dock Score energy function is used to rank the top potential TCM compounds; the chemical scaffold of top four TCM candidates with high binding affinity is displayed in Figure 2 with its scoring function and sources. The top four TCM compounds, trichosanatine, angeliferulate, dichotomoside E, and squamosamide, were extracted from Trichosanthes rosthornii Harms, Angelica sinensis, Stellaria dichotoma L., and Annona squamosa L., respectively. After the virtual screening, the docking poses of top four TCM compounds in the binding domain of PP2A-α are displayed in Figure 3. All the top four TCM compounds have interactions with key residues Arg89 and Arg214. Trichosanatine exists hydrogen bonds (H-bonds) with key residues Arg89 and Arg214. Angeliferulate has H-bonds with residues Arg89, Gln122, Arg214, and a π interaction with residue Trp200. Dichotomoside E forms H-bonds with residues Arg89, Tyr127, Gly215, and a π interaction with residue Arg214. Squamosamide has both H-bond and π interaction with residue Arg214. In addition, there exist H-bonds with residue Leu243 and a π interaction with residue Arg89. Those interactions hold the top four TCM compounds in the binding domain of PP2A-α protein.

Bottom Line: As an environmental toxin, okadaic acid, is a tumor promoter and binds to PP2A catalytic C subunit and the cancer-associated mutations in PP2A structural A subunit in human tumor tissue; PP2A may have tumor-suppressing function.The results of docking simulation are optimized under dynamic conditions by MD simulations after virtual screening to validate the stability of H-bonds between PP2A- α protein and each ligand.Hence, we propose the TCM compounds, trichosanatine and squamosamide, as potential candidates as lead compounds for further study in drug development process with the PP2A- α protein.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, China Medical University, Taichung 40402, Taiwan.

ABSTRACT
Protein phosphatase 2A (PP2A) is an important phosphatase which regulates various cellular processes, such as protein synthesis, cell growth, cellular signaling, apoptosis, metabolism, and stress responses. It is a holoenzyme composed of the structural A and catalytic C subunits and a regulatory B subunit. As an environmental toxin, okadaic acid, is a tumor promoter and binds to PP2A catalytic C subunit and the cancer-associated mutations in PP2A structural A subunit in human tumor tissue; PP2A may have tumor-suppressing function. It is a potential drug target in the treatment of cancer. In this study, we screen the TCM compounds in TCM Database@Taiwan to investigate the potent lead compounds as PP2A agent. The results of docking simulation are optimized under dynamic conditions by MD simulations after virtual screening to validate the stability of H-bonds between PP2A- α protein and each ligand. The top TCM candidates, trichosanatine and squamosamide, have potential binding affinities and interactions with key residues Arg89 and Arg214 in the docking simulation. In addition, these interactions were stable under dynamic conditions. Hence, we propose the TCM compounds, trichosanatine and squamosamide, as potential candidates as lead compounds for further study in drug development process with the PP2A- α protein.

No MeSH data available.


Related in: MedlinePlus