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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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Chemical scaffold of controls and top three TCM candidates with their scoring function and sources.
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fig3: Chemical scaffold of controls and top three TCM candidates with their scoring function and sources.

Mentions: Before virtual screening, the cocrystallized antitumor agent, LY2940680, had been redocked by LigandFit protocol into the binding site defined by the volume of LY2940680 (Figure 2(a)) to validate the accuracy of LigandFit protocol. The Root-mean-square deviation value between crystallized structure and docking pose of LY2940680 is 0.5106 Å (Figure 2(b)). After virtual screening, the chemical scaffold top TCM compounds ranked by Dock Score [43] and LY2940680 are illustrated in Figure 3. The scoring function of Dock Score indicates that the top three TCM compounds have higher binding affinities than LY2940680. The top three TCM compounds, precatorine, labiatic acid, and 2,2′-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid), are extracted from Abrus precatorius L., Rosmarinus officinalis L., and Ardisia japonica, respectively. According to the docking poses in Figure 4, for positive control, LY2940680, there exists a π interaction with residue Phe484 and hydrogen bonds (H-bonds) with residues Asn219 and Arg400. Precatorine has π interactions with residues Tyr394, Arg400, Phe484, and H-bonds with residue Lys395. Labiatic acid has a π interaction with residue Phe484 and H-bonds with residues Tyr207, Lys395, and Arg400. The top 3 compounds have π interactions with residues Tyr394, Arg400, Phe484, and H-bonds with resides Tyr394, Lys395, His470, and Asn521. The docking poses displayed in Figure 4 indicate that each compound has a π interaction with residue Phe484 and interaction with common residues Lys395 and Arg400. Those interactions stabilize each compound in the binding domain of Smo protein.


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)

Chemical scaffold of controls and top three TCM candidates with their scoring function and sources.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Chemical scaffold of controls and top three TCM candidates with their scoring function and sources.
Mentions: Before virtual screening, the cocrystallized antitumor agent, LY2940680, had been redocked by LigandFit protocol into the binding site defined by the volume of LY2940680 (Figure 2(a)) to validate the accuracy of LigandFit protocol. The Root-mean-square deviation value between crystallized structure and docking pose of LY2940680 is 0.5106 Å (Figure 2(b)). After virtual screening, the chemical scaffold top TCM compounds ranked by Dock Score [43] and LY2940680 are illustrated in Figure 3. The scoring function of Dock Score indicates that the top three TCM compounds have higher binding affinities than LY2940680. The top three TCM compounds, precatorine, labiatic acid, and 2,2′-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid), are extracted from Abrus precatorius L., Rosmarinus officinalis L., and Ardisia japonica, respectively. According to the docking poses in Figure 4, for positive control, LY2940680, there exists a π interaction with residue Phe484 and hydrogen bonds (H-bonds) with residues Asn219 and Arg400. Precatorine has π interactions with residues Tyr394, Arg400, Phe484, and H-bonds with residue Lys395. Labiatic acid has a π interaction with residue Phe484 and H-bonds with residues Tyr207, Lys395, and Arg400. The top 3 compounds have π interactions with residues Tyr394, Arg400, Phe484, and H-bonds with resides Tyr394, Lys395, His470, and Asn521. The docking poses displayed in Figure 4 indicate that each compound has a π interaction with residue Phe484 and interaction with common residues Lys395 and Arg400. Those interactions stabilize each compound in the binding domain of Smo protein.

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