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Potential smoothened inhibitor from traditional Chinese medicine against the disease of diabetes, obesity, and cancer.

Chen KC, Sun MF, Chen HY, Lee CC, Chen CY - Biomed Res Int (2014)

Bottom Line: For the mechanisms of diseases, the hedgehog signaling pathway plays an important role in body patterning during embryogenesis.After MD simulations, which can optimize the result of docking simulation and validate the stability of H-bonds between each ligand and Smo protein under dynamic conditions, top three TCM compounds maintain most of interactions with Smo protein, which keep the ligand binding stable in the binding domain.Hence, we propose precatorine, labiatic acid, and 2,2'-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid) as potential lead compounds for further study in drug development process with the Smo protein.

View Article: PubMed Central - PubMed

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

ABSTRACT
Nowadays, obesity becomes a serious global problem, which can induce a series of diseases such as type 2 diabetes mellitus, cancer, cardiovascular disease, metabolic syndrome, and stoke. For the mechanisms of diseases, the hedgehog signaling pathway plays an important role in body patterning during embryogenesis. For this reason, smoothened homologue (Smo) protein had been indicated as the drug target. In addition, the small-molecule Smo inhibitor had also been used in oncology clinical trials. To improve drug development of TCM compounds, we aim to investigate the potent lead compounds as Smo inhibitor from the TCM compounds in TCM Database@Taiwan. The top three TCM compounds, precatorine, labiatic acid, and 2,2'-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid), have displayed higher potent binding affinities than the positive control, LY2940680, in the docking simulation. After MD simulations, which can optimize the result of docking simulation and validate the stability of H-bonds between each ligand and Smo protein under dynamic conditions, top three TCM compounds maintain most of interactions with Smo protein, which keep the ligand binding stable in the binding domain. Hence, we propose precatorine, labiatic acid, and 2,2'-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid) as potential lead compounds for further study in drug development process with the Smo protein.

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Distances of hydrogen bonds with common residues during 5000 ps of MD simulation.
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fig13: Distances of hydrogen bonds with common residues during 5000 ps of MD simulation.

Mentions: To analyze the variation of H-bonds for key residues in each protein-ligand complex, the H-bond occupancy for key residues of Smo protein with top three candidates and LY2940680 overall 5000 ps of MD simulation was listed in Table 1, and the distance variations of each H-bond were displayed in Figure 13. They indicate that the H-bonds between LY2940680 and residues Asn219, Tyr394, Arg400 were stabilized over 5000 ps of MD simulation. In addition, the H-bonds between top three TCM compounds and residues mentioned above were also stabilized. Comparing to docking poses between docking simulation (Figure 4) and MD simulation (Figure 12), LY2940680 and the top three TCM compounds maintain most of interactions with Smo protein, which keep the ligand binding stable in the binding domain.


Potential smoothened inhibitor from traditional Chinese medicine against the disease of diabetes, obesity, and cancer.

Chen KC, Sun MF, Chen HY, Lee CC, Chen CY - Biomed Res Int (2014)

Distances of hydrogen bonds with common residues during 5000 ps of MD simulation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4127221&req=5

fig13: Distances of hydrogen bonds with common residues during 5000 ps of MD simulation.
Mentions: To analyze the variation of H-bonds for key residues in each protein-ligand complex, the H-bond occupancy for key residues of Smo protein with top three candidates and LY2940680 overall 5000 ps of MD simulation was listed in Table 1, and the distance variations of each H-bond were displayed in Figure 13. They indicate that the H-bonds between LY2940680 and residues Asn219, Tyr394, Arg400 were stabilized over 5000 ps of MD simulation. In addition, the H-bonds between top three TCM compounds and residues mentioned above were also stabilized. Comparing to docking poses between docking simulation (Figure 4) and MD simulation (Figure 12), LY2940680 and the top three TCM compounds maintain most of interactions with Smo protein, which keep the ligand binding stable in the binding domain.

Bottom Line: For the mechanisms of diseases, the hedgehog signaling pathway plays an important role in body patterning during embryogenesis.After MD simulations, which can optimize the result of docking simulation and validate the stability of H-bonds between each ligand and Smo protein under dynamic conditions, top three TCM compounds maintain most of interactions with Smo protein, which keep the ligand binding stable in the binding domain.Hence, we propose precatorine, labiatic acid, and 2,2'-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid) as potential lead compounds for further study in drug development process with the Smo protein.

View Article: PubMed Central - PubMed

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

ABSTRACT
Nowadays, obesity becomes a serious global problem, which can induce a series of diseases such as type 2 diabetes mellitus, cancer, cardiovascular disease, metabolic syndrome, and stoke. For the mechanisms of diseases, the hedgehog signaling pathway plays an important role in body patterning during embryogenesis. For this reason, smoothened homologue (Smo) protein had been indicated as the drug target. In addition, the small-molecule Smo inhibitor had also been used in oncology clinical trials. To improve drug development of TCM compounds, we aim to investigate the potent lead compounds as Smo inhibitor from the TCM compounds in TCM Database@Taiwan. The top three TCM compounds, precatorine, labiatic acid, and 2,2'-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid), have displayed higher potent binding affinities than the positive control, LY2940680, in the docking simulation. After MD simulations, which can optimize the result of docking simulation and validate the stability of H-bonds between each ligand and Smo protein under dynamic conditions, top three TCM compounds maintain most of interactions with Smo protein, which keep the ligand binding stable in the binding domain. Hence, we propose precatorine, labiatic acid, and 2,2'-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid) as potential lead compounds for further study in drug development process with the Smo protein.

Show MeSH
Related in: MedlinePlus