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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

Analysis of transport pathways for IDH2 R140Q mutant protein complexes with (a) AGI-6780, (b) precatorine, and (c) abrine.
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Related In: Results  -  Collection


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fig13: Analysis of transport pathways for IDH2 R140Q mutant protein complexes with (a) AGI-6780, (b) precatorine, and (c) abrine.

Mentions: After MD simulation, we identify the representative structures of IDH2 R140Q mutant proteins in apo form and in each complex using the RMSD values and graphical depiction of the clusters analysis with a RMSD cutoff of 0.105 nm in Figure 11. The docking poses of the representative structures for complexes of IDH2 R140Q mutant proteins with AGI-6780, precatorine, and abrine are illustrated in Figure 12. To compare with the result in docking simulation, the IDH2 R140Q mutant protein inhibitor, AGI-6780, has stable hydrogen bonds (H-bonds) with residues Gln316 in both chains of IDH2 R140Q mutant protein and forms a π interaction with residue Val315 in chain B of IDH2 R140Q mutant protein. For TCM candidates, they have similar docking poses as docking simulation, which has stable H-bonds with residues Gln316. The H-bond occupancy for key residues in complexes of IDH2 R140Q mutant protein with AGI-6780 and top TCM compounds overall 5000 ps of molecular dynamics simulation in Table 1 displayed the stability of H-bonds. Analysis of transport pathways for each IDH2 R140Q mutant protein complex illustrated in Figure 13 shows the presumably pathways for small molecule. They indicate that IDH2 R140Q mutant protein docking with precatorine and abrine has similar effects of protein conformation 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)

Analysis of transport pathways for IDH2 R140Q mutant protein complexes with (a) AGI-6780, (b) precatorine, and (c) abrine.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig13: Analysis of transport pathways for IDH2 R140Q mutant protein complexes with (a) AGI-6780, (b) precatorine, and (c) abrine.
Mentions: After MD simulation, we identify the representative structures of IDH2 R140Q mutant proteins in apo form and in each complex using the RMSD values and graphical depiction of the clusters analysis with a RMSD cutoff of 0.105 nm in Figure 11. The docking poses of the representative structures for complexes of IDH2 R140Q mutant proteins with AGI-6780, precatorine, and abrine are illustrated in Figure 12. To compare with the result in docking simulation, the IDH2 R140Q mutant protein inhibitor, AGI-6780, has stable hydrogen bonds (H-bonds) with residues Gln316 in both chains of IDH2 R140Q mutant protein and forms a π interaction with residue Val315 in chain B of IDH2 R140Q mutant protein. For TCM candidates, they have similar docking poses as docking simulation, which has stable H-bonds with residues Gln316. The H-bond occupancy for key residues in complexes of IDH2 R140Q mutant protein with AGI-6780 and top TCM compounds overall 5000 ps of molecular dynamics simulation in Table 1 displayed the stability of H-bonds. Analysis of transport pathways for each IDH2 R140Q mutant protein complex illustrated in Figure 13 shows the presumably pathways for small molecule. They indicate that IDH2 R140Q mutant protein docking with precatorine and abrine has similar effects of protein conformation 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