Limits...
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

Root-mean-square deviation value (a) and graphical depiction of the clusters with cutoff 0.1 nm (d) for PP2A protein complexes with trichosanatine, angeliferulate, dichotomoside E, and squamosamide.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4020536&req=5

fig7: Root-mean-square deviation value (a) and graphical depiction of the clusters with cutoff 0.1 nm (d) for PP2A protein complexes with trichosanatine, angeliferulate, dichotomoside E, and squamosamide.

Mentions: In LigandFit protocol, each compound was docked into binding site using a shape-based docking with rigid body of PP2A-α protein. The interactions between each compound and PP2A-α protein mention above may not be stable under dynamic conditions. We employed MD simulation for each protein-ligand complex to study the stability of interactions for each docking pose. The information of root-mean-square deviations (RMSDs) and total energies over 5000 ps of MD simulation is displayed in Figure 4. It indicates that the atomic fluctuations of protein complexes with top four TCM compounds tend to be stable after 4800 ps of MD simulation, and there is no significant variation in the total energies for each complex during MD simulation. To analyze the possible effect of each top TCM candidate for the PP2A-α protein, Figure 5 displays the variation of solvent accessible surface area for PP2A-α protein over 5000 ps of MD simulation. For top four TCM candidates, they have similar hydrophobic and hydrophilic surface areas when the MD simulation tends to be stable, which indicates that those compounds may not affect the sharpness of PP2A-α protein after they dock in the binding domain. Figure 6 illustrates the root-mean-square fluctuation of each residue of PP2A-α protein during 5000 ps of MD simulation. It indicates that they have similar deviation for key residues in the binding domain of PP2A-α protein during 5000 ps of MD simulation. In Figure 7, root-mean-square deviation value for each PP2A-α protein complex illustrates the RMSD values between each MD trajectory of 5000 ps of MD simulation, and graphical depiction of the clusters with cutoff 0.1 nm is employed to define the middle RMSD structure in the major cluster as the representative structures for each complex after MD simulation. The docking poses of the representative structures for each protein-ligand complex are illustrated in Figure 8. For angeliferulate and dichotomoside E, the interactions between protein and ligand mention in docking simulation are not stable under dynamic conditions, which indicates that those two TCM compounds cannot binding stabilized in the binding domain of PP2A-α protein. For trichosanatine, the representative docking poses in 4.82 ns indicate that it has similar docking pose as mentioned in docking simulation and maintains the H-bond with key residue Arg89. In addition, it forms H-bonds and π interactions with residues His118, Tyr127, and Trp200 after MD simulation. The docking pose of squamosamide in 4.82 ns of MD simulation also has similar docking pose as mentioned in docking simulation and maintains the H-bond and π interactions with key residue Arg214 and H-bond with Leu243. To analyze the stability of these H-bonds, the occupancy of H-bonds overall 5000 ps of molecular dynamics simulation are listed in Table 1, and the variations of distance for each H-bond in the PP2A-α protein complexes with trichosanatine and squamosamide are illustrated in Figure 9. For trichosanatine, it has stable H-bonds with residues Arg89 and His118, and the distances with residues Arg214 are stable in 0.4 nm. For squamosamide, it has stable H-bonds with residues Arg214 and Leu243.


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

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

Root-mean-square deviation value (a) and graphical depiction of the clusters with cutoff 0.1 nm (d) for PP2A protein complexes with trichosanatine, angeliferulate, dichotomoside E, and squamosamide.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig7: Root-mean-square deviation value (a) and graphical depiction of the clusters with cutoff 0.1 nm (d) for PP2A protein complexes with trichosanatine, angeliferulate, dichotomoside E, and squamosamide.
Mentions: In LigandFit protocol, each compound was docked into binding site using a shape-based docking with rigid body of PP2A-α protein. The interactions between each compound and PP2A-α protein mention above may not be stable under dynamic conditions. We employed MD simulation for each protein-ligand complex to study the stability of interactions for each docking pose. The information of root-mean-square deviations (RMSDs) and total energies over 5000 ps of MD simulation is displayed in Figure 4. It indicates that the atomic fluctuations of protein complexes with top four TCM compounds tend to be stable after 4800 ps of MD simulation, and there is no significant variation in the total energies for each complex during MD simulation. To analyze the possible effect of each top TCM candidate for the PP2A-α protein, Figure 5 displays the variation of solvent accessible surface area for PP2A-α protein over 5000 ps of MD simulation. For top four TCM candidates, they have similar hydrophobic and hydrophilic surface areas when the MD simulation tends to be stable, which indicates that those compounds may not affect the sharpness of PP2A-α protein after they dock in the binding domain. Figure 6 illustrates the root-mean-square fluctuation of each residue of PP2A-α protein during 5000 ps of MD simulation. It indicates that they have similar deviation for key residues in the binding domain of PP2A-α protein during 5000 ps of MD simulation. In Figure 7, root-mean-square deviation value for each PP2A-α protein complex illustrates the RMSD values between each MD trajectory of 5000 ps of MD simulation, and graphical depiction of the clusters with cutoff 0.1 nm is employed to define the middle RMSD structure in the major cluster as the representative structures for each complex after MD simulation. The docking poses of the representative structures for each protein-ligand complex are illustrated in Figure 8. For angeliferulate and dichotomoside E, the interactions between protein and ligand mention in docking simulation are not stable under dynamic conditions, which indicates that those two TCM compounds cannot binding stabilized in the binding domain of PP2A-α protein. For trichosanatine, the representative docking poses in 4.82 ns indicate that it has similar docking pose as mentioned in docking simulation and maintains the H-bond with key residue Arg89. In addition, it forms H-bonds and π interactions with residues His118, Tyr127, and Trp200 after MD simulation. The docking pose of squamosamide in 4.82 ns of MD simulation also has similar docking pose as mentioned in docking simulation and maintains the H-bond and π interactions with key residue Arg214 and H-bond with Leu243. To analyze the stability of these H-bonds, the occupancy of H-bonds overall 5000 ps of molecular dynamics simulation are listed in Table 1, and the variations of distance for each H-bond in the PP2A-α protein complexes with trichosanatine and squamosamide are illustrated in Figure 9. For trichosanatine, it has stable H-bonds with residues Arg89 and His118, and the distances with residues Arg214 are stable in 0.4 nm. For squamosamide, it has stable H-bonds with residues Arg214 and Leu243.

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