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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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Docking poses of middle RMSD structure in the major cluster for 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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fig12: Docking poses of middle RMSD structure in the major cluster for Smo protein complexes with LY2940680, precatorine, labiatic acid, and 2,2′-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid).

Mentions: For the MD simulation, the representative structures of each complex under dynamic conditions were identified by the cluster analysis with a RMSD cutoff of 0.105 nm. According to the RMSD values and graphical depiction of the clusters for Smo protein complexes with LY2940680, precatorine, labiatic acid, and 2,2′-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid) illustrated in Figure 11, the docking poses of the representative structures for Smo protein complex with LY2940680 and the top three TCM compounds were illustrated in Figure 12. For LY2940680, there exist the stable H-bonds with residues Asn219 and Arg400 under dynamic conditions. In addition, it forms an H-bond with Tyr394 after MD simulation. Precatorine has stable π interactions with residue Phe484 and H-bonds with Lys395. After MD simulation, it forms an H-bond with residue Asn219. Labiatic acid has stable H-bonds with residues Tyr207, Lys395 and forms the H-bonds with residues Asp384, Gln477, and Glu518. The top 3 TCM compounds have stable π interactions with residue Phe484 and H-bonds with residue Lys395. Moreover, the interaction with residue Arg400 was changed from π interaction to H-bond and forms the H-bonds with residues Tyr207 and Arg285 after MD simulation.


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)

Docking poses of middle RMSD structure in the major cluster for 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

fig12: Docking poses of middle RMSD structure in the major cluster for Smo protein complexes with LY2940680, precatorine, labiatic acid, and 2,2′-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid).
Mentions: For the MD simulation, the representative structures of each complex under dynamic conditions were identified by the cluster analysis with a RMSD cutoff of 0.105 nm. According to the RMSD values and graphical depiction of the clusters for Smo protein complexes with LY2940680, precatorine, labiatic acid, and 2,2′-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid) illustrated in Figure 11, the docking poses of the representative structures for Smo protein complex with LY2940680 and the top three TCM compounds were illustrated in Figure 12. For LY2940680, there exist the stable H-bonds with residues Asn219 and Arg400 under dynamic conditions. In addition, it forms an H-bond with Tyr394 after MD simulation. Precatorine has stable π interactions with residue Phe484 and H-bonds with Lys395. After MD simulation, it forms an H-bond with residue Asn219. Labiatic acid has stable H-bonds with residues Tyr207, Lys395 and forms the H-bonds with residues Asp384, Gln477, and Glu518. The top 3 TCM compounds have stable π interactions with residue Phe484 and H-bonds with residue Lys395. Moreover, the interaction with residue Arg400 was changed from π interaction to H-bond and forms the H-bonds with residues Tyr207 and Arg285 after MD simulation.

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