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Potential mitochondrial isocitrate dehydrogenase R140Q mutant inhibitor from traditional Chinese medicine against cancers.

Lee WY, Chen KC, Chen HY, Chen CY - Biomed Res Int (2014)

Bottom Line: Comparing to the IDH2 R140Q mutant protein inhibitor, AGI-6780, the top two TCM compounds, precatorine and abrine, have higher binding affinities with target protein in docking simulation.After MD simulation, the top two TCM compounds remain as the same docking poses under dynamic conditions.In addition, precatorine is extracted from Abrus precatorius L., which represents the cytotoxic and proapoptotic effects for breast cancer and several tumor lines.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Informatics, Asia University, Taichung 41354, Taiwan ; School of Medicine, College of Medicine, China Medical University, Taichung 40402, Taiwan ; Department of Neurosurgery, China Medical University Hospital, Taichung 40447, Taiwan.

ABSTRACT
A recent research of cancer has indicated that the mutant of isocitrate dehydrogenase 1 and 2 (IDH1 and 2) genes will induce various cancers, including chondrosarcoma, cholangiocarcinomas, and acute myelogenous leukemia due to the effect of point mutations in the active-site arginine residues of isocitrate dehydrogenase (IDH), such as IDH1/R132, IDH2/R140, and IDH2/R172. As the inhibition for those tumor-associated mutant IDH proteins may induce differentiation of those cancer cells, these tumor-associated mutant IDH proteins can be treated as a drug target proteins for a differentiation therapy against cancers. In this study, we aim to identify the potent TCM compounds from the TCM Database@Taiwan as lead compounds of IDH2 R140Q mutant inhibitor. Comparing to the IDH2 R140Q mutant protein inhibitor, AGI-6780, the top two TCM compounds, precatorine and abrine, have higher binding affinities with target protein in docking simulation. After MD simulation, the top two TCM compounds remain as the same docking poses under dynamic conditions. In addition, precatorine is extracted from Abrus precatorius L., which represents the cytotoxic and proapoptotic effects for breast cancer and several tumor lines. Hence, we propose the TCM compounds, precatorine and abrine, as potential candidates as lead compounds for further study in drug development process with the IDH2 R140Q mutant protein against cancer.

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Related in: MedlinePlus

Mean square displacement (MSD) for (a) protein and (b) ligand over 5000 ps of MD simulation for IDH2 R140Q mutant proteins and protein complexes with AGI-6780, precatorine, and abrine.
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fig9: Mean square displacement (MSD) for (a) protein and (b) ligand over 5000 ps of MD simulation for IDH2 R140Q mutant proteins and protein complexes with AGI-6780, precatorine, and abrine.

Mentions: For the docking simulation performed by LigandFit protocol, the receptor is a rigid body of IDH2 R140Q mutant proteins. The conformation of the IDH2 R140Q mutant protein may modify under dynamic conditions. We employed the MD simulation to validate the stability of interactions between IDH2 R140Q mutant proteins and each ligand. RMSDs illustrated the atomic fluctuations during MD simulation. Figure 5 displays the atomic fluctuations of IDH2 R140Q mutant proteins in apo form and complexes with AGI-6780, precatorine, and abrine and the atomic fluctuations of each compound during 5000 ps MD simulation. It shows that IDH2 R140Q mutant proteins tend to be stable after first 100 ps MD simulation, but the ligands except precatorine are fluctuate during MD simulation. To consider the variation radii of gyration for protein and total energy over 5000 ps MD simulation in Figure 6, it indicates that the radii of gyration for IDH2 R140Q mutant proteins in apo form were decreased after 4500 ps MD simulation, but the radii of gyration for complexes of IDH2 R140Q mutant proteins with AGI-6780, precatorine, and abrine were more stabilized. In addition, there is no significant change for the total energies of each IDH2 R140Q mutant protein complex during MD simulation in Figure 7. The variation of solvent accessible surface area over 5000 ps MD simulation in Figure 8 indicates that docking the ligands, AGI-6780, precatorine, and abrine, would not affect the solvent accessible surface of IDH2 R140Q mutant protein under dynamic conditions. The mean square displacement (MSD) for each protein and ligand in IDH2 R140Q mutant proteins and protein complexes with AGI-6780, precatorine, and abrine over 5000 ps of MD simulation is displayed in Figure 9. Root-mean-square fluctuation (RMSF) for each residue over 5000 ps MD simulation is displayed in Figure 10. They indicate that IDH2 R140Q mutant protein docking with precatorine and abrine causes similar diffusion constant and flexibility for IDH2 R140Q mutant proteins as AGI-6780.


Potential mitochondrial isocitrate dehydrogenase R140Q mutant inhibitor from traditional Chinese medicine against cancers.

Lee WY, Chen KC, Chen HY, Chen CY - Biomed Res Int (2014)

Mean square displacement (MSD) for (a) protein and (b) ligand over 5000 ps of MD simulation for IDH2 R140Q mutant proteins and protein complexes with AGI-6780, precatorine, and abrine.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4066711&req=5

fig9: Mean square displacement (MSD) for (a) protein and (b) ligand over 5000 ps of MD simulation for IDH2 R140Q mutant proteins and protein complexes with AGI-6780, precatorine, and abrine.
Mentions: For the docking simulation performed by LigandFit protocol, the receptor is a rigid body of IDH2 R140Q mutant proteins. The conformation of the IDH2 R140Q mutant protein may modify under dynamic conditions. We employed the MD simulation to validate the stability of interactions between IDH2 R140Q mutant proteins and each ligand. RMSDs illustrated the atomic fluctuations during MD simulation. Figure 5 displays the atomic fluctuations of IDH2 R140Q mutant proteins in apo form and complexes with AGI-6780, precatorine, and abrine and the atomic fluctuations of each compound during 5000 ps MD simulation. It shows that IDH2 R140Q mutant proteins tend to be stable after first 100 ps MD simulation, but the ligands except precatorine are fluctuate during MD simulation. To consider the variation radii of gyration for protein and total energy over 5000 ps MD simulation in Figure 6, it indicates that the radii of gyration for IDH2 R140Q mutant proteins in apo form were decreased after 4500 ps MD simulation, but the radii of gyration for complexes of IDH2 R140Q mutant proteins with AGI-6780, precatorine, and abrine were more stabilized. In addition, there is no significant change for the total energies of each IDH2 R140Q mutant protein complex during MD simulation in Figure 7. The variation of solvent accessible surface area over 5000 ps MD simulation in Figure 8 indicates that docking the ligands, AGI-6780, precatorine, and abrine, would not affect the solvent accessible surface of IDH2 R140Q mutant protein under dynamic conditions. The mean square displacement (MSD) for each protein and ligand in IDH2 R140Q mutant proteins and protein complexes with AGI-6780, precatorine, and abrine over 5000 ps of MD simulation is displayed in Figure 9. Root-mean-square fluctuation (RMSF) for each residue over 5000 ps MD simulation is displayed in Figure 10. They indicate that IDH2 R140Q mutant protein docking with precatorine and abrine causes similar diffusion constant and flexibility for IDH2 R140Q mutant proteins as AGI-6780.

Bottom Line: Comparing to the IDH2 R140Q mutant protein inhibitor, AGI-6780, the top two TCM compounds, precatorine and abrine, have higher binding affinities with target protein in docking simulation.After MD simulation, the top two TCM compounds remain as the same docking poses under dynamic conditions.In addition, precatorine is extracted from Abrus precatorius L., which represents the cytotoxic and proapoptotic effects for breast cancer and several tumor lines.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Informatics, Asia University, Taichung 41354, Taiwan ; School of Medicine, College of Medicine, China Medical University, Taichung 40402, Taiwan ; Department of Neurosurgery, China Medical University Hospital, Taichung 40447, Taiwan.

ABSTRACT
A recent research of cancer has indicated that the mutant of isocitrate dehydrogenase 1 and 2 (IDH1 and 2) genes will induce various cancers, including chondrosarcoma, cholangiocarcinomas, and acute myelogenous leukemia due to the effect of point mutations in the active-site arginine residues of isocitrate dehydrogenase (IDH), such as IDH1/R132, IDH2/R140, and IDH2/R172. As the inhibition for those tumor-associated mutant IDH proteins may induce differentiation of those cancer cells, these tumor-associated mutant IDH proteins can be treated as a drug target proteins for a differentiation therapy against cancers. In this study, we aim to identify the potent TCM compounds from the TCM Database@Taiwan as lead compounds of IDH2 R140Q mutant inhibitor. Comparing to the IDH2 R140Q mutant protein inhibitor, AGI-6780, the top two TCM compounds, precatorine and abrine, have higher binding affinities with target protein in docking simulation. After MD simulation, the top two TCM compounds remain as the same docking poses under dynamic conditions. In addition, precatorine is extracted from Abrus precatorius L., which represents the cytotoxic and proapoptotic effects for breast cancer and several tumor lines. Hence, we propose the TCM compounds, precatorine and abrine, as potential candidates as lead compounds for further study in drug development process with the IDH2 R140Q mutant protein against cancer.

Show MeSH
Related in: MedlinePlus