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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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Total energy for complex over 5000 ps of MD simulation in Smo protein complexes with LY2940680, precatorine, labiatic acid, and 2,2′-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid).
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fig6: Total energy for complex over 5000 ps of MD simulation in Smo protein complexes with LY2940680, precatorine, labiatic acid, and 2,2′-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid).

Mentions: The docking simulation performed by LigandFit protocol docks compounds into binding site using a shape-based docking. Although the Monte-Carlo techniques had been employed to simulate the flexible compound by generating sets of compound conformations, the structure of target protein is a rigid body of Smo protein from the crystal structure. As the interactions between protein and ligand in the docking simulation may not be stable under dynamic conditions, the molecular dynamics (MD) simulations were performed to validate the stability of those interactions. The root-mean-square deviations (RMSDs) for each protein and ligand were displayed in Figure 5. They indicate the atomic fluctuations during MD simulation for each protein and ligand. Figure 5 shows that the atomic fluctuations of each complex tend to be stable after 4700 ps of MD simulation. The variations of total energy for each complex during 5000 ps of MD simulation were illustrated in Figure 6, which indicate that Smo protein docking with the top three TCM compounds has similar variation of total energy, and there is no significant change of total energy for each complex during 5000 ps of MD simulation. The variation of radius of gyration and mean square displacement (MSD) for proteins in each complex during 5000 ps of MD simulation was illustrated in Figures 7 and 8, respectively. They indicate that Smo protein docking with the top three TCM compounds has similar compactness and diffusion constant under dynamic conditions as LY2940680. The variation of solvent accessible surface area in Figure 9 can also be used to discuss the effect of each ligand for the Smo protein after docking. In Figure 9, it can be seen clearly that the Smo protein in each complex has similar solvent accessible surface area when the RMSDs tend to be stable after 4700 ps of MD simulation. The smallest distance between residue pairs for Smo protein in each complex illustrated in Figure 10 also has similar distance matrices. They indicate that the top three TCM compounds may cause similar influence for Smo protein as LY2940680.


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)

Total energy for complex over 5000 ps of MD simulation in Smo protein complexes with LY2940680, precatorine, labiatic acid, and 2,2′-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid).
© Copyright Policy
Related In: Results  -  Collection

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

fig6: Total energy for complex over 5000 ps of MD simulation in Smo protein complexes with LY2940680, precatorine, labiatic acid, and 2,2′-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid).
Mentions: The docking simulation performed by LigandFit protocol docks compounds into binding site using a shape-based docking. Although the Monte-Carlo techniques had been employed to simulate the flexible compound by generating sets of compound conformations, the structure of target protein is a rigid body of Smo protein from the crystal structure. As the interactions between protein and ligand in the docking simulation may not be stable under dynamic conditions, the molecular dynamics (MD) simulations were performed to validate the stability of those interactions. The root-mean-square deviations (RMSDs) for each protein and ligand were displayed in Figure 5. They indicate the atomic fluctuations during MD simulation for each protein and ligand. Figure 5 shows that the atomic fluctuations of each complex tend to be stable after 4700 ps of MD simulation. The variations of total energy for each complex during 5000 ps of MD simulation were illustrated in Figure 6, which indicate that Smo protein docking with the top three TCM compounds has similar variation of total energy, and there is no significant change of total energy for each complex during 5000 ps of MD simulation. The variation of radius of gyration and mean square displacement (MSD) for proteins in each complex during 5000 ps of MD simulation was illustrated in Figures 7 and 8, respectively. They indicate that Smo protein docking with the top three TCM compounds has similar compactness and diffusion constant under dynamic conditions as LY2940680. The variation of solvent accessible surface area in Figure 9 can also be used to discuss the effect of each ligand for the Smo protein after docking. In Figure 9, it can be seen clearly that the Smo protein in each complex has similar solvent accessible surface area when the RMSDs tend to be stable after 4700 ps of MD simulation. The smallest distance between residue pairs for Smo protein in each complex illustrated in Figure 10 also has similar distance matrices. They indicate that the top three TCM compounds may cause similar influence for Smo protein as LY2940680.

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