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. 2014:2014:385120.
doi: 10.1155/2014/385120. Epub 2014 May 6.

Design of glucagon-like Peptide-1 receptor agonist for diabetes mellitus from traditional chinese medicine

Hsin-Chieh Tang  1 , Calvin Yu-Chian Chen  2
Affiliations

Design of glucagon-like Peptide-1 receptor agonist for diabetes mellitus from traditional chinese medicine

Hsin-Chieh Tang et al. Evid Based Complement Alternat Med. 2014.

Abstract

Glucagon-like peptide-1 (GLP-1) is a promising target for diabetes mellitus (DM) therapy and reduces the occurrence of diabetes due to obesity. However, GLP-1 will be hydrolyzed soon by the enzyme dipeptidyl peptidase-4 (DPP-4). We tried to design small molecular drugs for GLP-1 receptor agonist from the world's largest traditional Chinese medicine (TCM) Database@Taiwan. According to docking results of virtual screening, we selected 2 TCM compounds, wenyujinoside and 28-deglucosylchikusetsusaponin IV, for further molecular dynamics (MD) simulation. GLP-1 was assigned as the control compound. Based on the results of root mean square deviation (RMSD), solvent accessible surface (SAS), mean square deviation (MSD), Gyrate, total energy, root mean square fluctuation (RMSF), matrices of smallest distance of residues, database of secondary structure assignment (DSSP), cluster analysis, and distance of H-bond, we concluded that all the 3 compounds could bind and activate GLP-1 receptor by computational simulation. Wenyujinoside and 28-deglucosylchikusetsusaponin IV were the TCM compounds that could be GLP-1 receptor agonists.

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Figures

Figure 1
Figure 1
Scaffold of top 2 TCM candidates: (a) wenyujinoside, (b) 28-deglucosylchikusetsusaponin IV, and the control: (c) glucagon-like peptide 1 (GLP1).
Figure 2
Figure 2
Docking poses by the LigandFit module in DS 2.5. (a) Wenyujinoside, (b) 28-deglucosylchikusetsusaponin IV, and the control: (c) GLP1.
Figure 3
Figure 3
Docking poses by the LIGPLOT program. (a) Wenyujinoside, (b) 28-deglucosylchikusetsusaponin IV, and the control: (c) GLP1.
Figure 4
Figure 4
Disorder disposition of GLP1 receptor structure. The most common key residues for all the 3 compounds are in the nondisordered region (below the red line).
Figure 5
Figure 5
(a) RMSD, (b) SAS, (c) MSD, and (d) Gyrate for wenyujinoside, 28-deglucosylchikusetsusaponin IV, GLP1 corresponding protein, and GLP1 receptor protein alone (apo).
Figure 6
Figure 6
Total energy for (a) wenyujinoside, (b) 28-deglucosylchikusetsusaponin IV, (c) GLP1 corresponding protein, and (d) GLP1 receptor protein alone (apo).
Figure 7
Figure 7
Root mean square fluctuation (RMSF) for wenyujinoside, 28-deglucosylchikusetsusaponin IV, GLP1 corresponding protein, and GLP1 receptor protein alone (apo).
Figure 8
Figure 8
Matrices of smallest distance of residues for (a) wenyujinoside, (b) 28-deglucosylchikusetsusaponin IV, (c) GLP1 corresponding protein, and (d) GLP1 receptor protein alone.
Figure 9
Figure 9
Database of secondary structure assignment (DSSP) and secondary structural feature ratio variations for (a) wenyujinoside, (b) 28-deglucosylchikusetsusaponin IV, (c) GLP1 corresponding protein, and (d) GLP1 receptor protein alone.
Figure 10
Figure 10
Distance of hydrogen bonds between wenyujinoside, 28-deglucosylchikusetsusaponin IV, GLP1, and essential amino acids of GLP1 receptor.
Figure 11
Figure 11
Cluster analysis for (a) wenyujinoside, (b) 28-deglucosylchikusetsusaponin IV, (c) GLP1 corresponding protein, and (d) GLP1 receptor protein alone.
Figure 12
Figure 12
Docking poses of MD. (a) Wenyujinoside, (b) 28-deglucosylchikusetsusaponin IV, and the control: (c) GLP1.
Figure 13
Figure 13
3D simulation of ligand pathway for (a) wenyujinoside, (b) 28-deglucosylchikusetsusaponin IV, and (c) GLP1 bound with GLP1 receptor protein.
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