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Interaction of Glucagon G-Protein Coupled Receptor with Known Natural Antidiabetic Compounds: Multiscoring In Silico Approach.

Baig MH, Ahmad K, Hasan Q, Khan MK, Rao NS, Kamal MA, Choi I - Evid Based Complement Alternat Med (2015)

Bottom Line: Among all selected natural compounds, curcumin was found to be the most effective compound against GCGR followed by amorfrutin 1 and 4-hydroxyderricin.These compounds were rescored to confirm the accuracy of binding using another scoring function (x-score).The final conclusions were drawn based on the results obtained from the GOLD and x-score.

View Article: PubMed Central - PubMed

Affiliation: School of Biotechnology, Yeungnam University, Gyeongsan 712749, Republic of Korea.

ABSTRACT
Glucagon receptor (GCGR) is a secretin-like (class B) family of G-protein coupled receptors (GPCRs) in humans that plays an important role in elevating the glucose concentration in blood and has thus become one of the promising therapeutic targets for treatment of type 2 diabetes mellitus. GCGR based inhibitors for the treatment of type 2 diabetes are either glucagon neutralizers or small molecular antagonists. Management of diabetes without any side effects is still a challenge to the medical system, and the search for a new and effective natural GCGR antagonist is an important area for the treatment of type 2 diabetes. In the present study, a number of natural compounds containing antidiabetic properties were selected from the literature and their binding potential against GCGR was determined using molecular docking and other in silico approaches. Among all selected natural compounds, curcumin was found to be the most effective compound against GCGR followed by amorfrutin 1 and 4-hydroxyderricin. These compounds were rescored to confirm the accuracy of binding using another scoring function (x-score). The final conclusions were drawn based on the results obtained from the GOLD and x-score. Further experiments were conducted to identify the atomic level interactions of selected compounds with GCGR.

No MeSH data available.


Related in: MedlinePlus

Binding of curcumin within the active site of GCGR.
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Related In: Results  -  Collection


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fig1: Binding of curcumin within the active site of GCGR.

Mentions: Glucagon G-protein coupled receptor, class B GPCR, has become a promising therapeutic drug target for the treatment of type 2 diabetes mellitus (T2DM) [35, 36]. Earlier studies have reported that blockade of glucagon receptor gene (GCGR) activity is useful for the treatment of T2DM [25, 35, 36]. However, management of diabetes without any side effects is still a challenge to the medical system [37]. This has led to increasing demand for natural products with antidiabetic activity with fewer or no side effects. Molecular docking is considered to be an important tool for investigation of the mode of interaction of ligands with the target and elucidation of the underlying binding mechanism [38, 39]. In this study, we determined the binding potential of several natural compounds with known antidiabetic properties against GCGR using molecular docking and other in silico approaches. The prime objective of the present study was to identify the binding potential of several natural antidiabetic compounds against GCGR using the molecular docking approach. In this regard, we used an in silico approach to identify natural compounds with the potential for use in the treatment of GCGR. Additionally, molecular docking simulation studies were conducted to investigate possible binding modes of all selected natural compounds against GCGR. Several plausible binding modes were detected and ranked based on their gold fitness score. Moreover, these compounds were rescored to confirm the accuracy of binding using another scoring function (x-score). The final conclusions were drawn based on the results obtained from GOLD and the x-score. Curcumin, a principal component of turmeric (Curcuma longa Linn.) and a popular spice in Asian cuisine, was found to be the most effective against GCGR (gold fitness score of 53.53), followed by amorfrutin 1, widely available traditional medicine isolated from licorice (Glycyrrhiza foetida), and 4-hydroxyderricin, isolated from root of A. keiskei, which were found to bind with gold fitness scores of 48.18 and 44.06, respectively. Rescoring of these docked results using x-score revealed that curcumin, amorfrutin 1, and 4-hydroxyderricin bind within the active site of GCGR with binding free energies of −8.35, −8.37, and −8.56 kcal/mol, respectively. Table 1 illustrates the binding score of the finally selected compounds against GCGR. The binding mode of the selected inhibitors within the active site of GCGR is shown in Figures 1–3. The results obtained from both scoring functions were also found to be in good agreement with each other. The scores obtained using all three functions are shown in the graph (Figure 4).


Interaction of Glucagon G-Protein Coupled Receptor with Known Natural Antidiabetic Compounds: Multiscoring In Silico Approach.

Baig MH, Ahmad K, Hasan Q, Khan MK, Rao NS, Kamal MA, Choi I - Evid Based Complement Alternat Med (2015)

Binding of curcumin within the active site of GCGR.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4508340&req=5

fig1: Binding of curcumin within the active site of GCGR.
Mentions: Glucagon G-protein coupled receptor, class B GPCR, has become a promising therapeutic drug target for the treatment of type 2 diabetes mellitus (T2DM) [35, 36]. Earlier studies have reported that blockade of glucagon receptor gene (GCGR) activity is useful for the treatment of T2DM [25, 35, 36]. However, management of diabetes without any side effects is still a challenge to the medical system [37]. This has led to increasing demand for natural products with antidiabetic activity with fewer or no side effects. Molecular docking is considered to be an important tool for investigation of the mode of interaction of ligands with the target and elucidation of the underlying binding mechanism [38, 39]. In this study, we determined the binding potential of several natural compounds with known antidiabetic properties against GCGR using molecular docking and other in silico approaches. The prime objective of the present study was to identify the binding potential of several natural antidiabetic compounds against GCGR using the molecular docking approach. In this regard, we used an in silico approach to identify natural compounds with the potential for use in the treatment of GCGR. Additionally, molecular docking simulation studies were conducted to investigate possible binding modes of all selected natural compounds against GCGR. Several plausible binding modes were detected and ranked based on their gold fitness score. Moreover, these compounds were rescored to confirm the accuracy of binding using another scoring function (x-score). The final conclusions were drawn based on the results obtained from GOLD and the x-score. Curcumin, a principal component of turmeric (Curcuma longa Linn.) and a popular spice in Asian cuisine, was found to be the most effective against GCGR (gold fitness score of 53.53), followed by amorfrutin 1, widely available traditional medicine isolated from licorice (Glycyrrhiza foetida), and 4-hydroxyderricin, isolated from root of A. keiskei, which were found to bind with gold fitness scores of 48.18 and 44.06, respectively. Rescoring of these docked results using x-score revealed that curcumin, amorfrutin 1, and 4-hydroxyderricin bind within the active site of GCGR with binding free energies of −8.35, −8.37, and −8.56 kcal/mol, respectively. Table 1 illustrates the binding score of the finally selected compounds against GCGR. The binding mode of the selected inhibitors within the active site of GCGR is shown in Figures 1–3. The results obtained from both scoring functions were also found to be in good agreement with each other. The scores obtained using all three functions are shown in the graph (Figure 4).

Bottom Line: Among all selected natural compounds, curcumin was found to be the most effective compound against GCGR followed by amorfrutin 1 and 4-hydroxyderricin.These compounds were rescored to confirm the accuracy of binding using another scoring function (x-score).The final conclusions were drawn based on the results obtained from the GOLD and x-score.

View Article: PubMed Central - PubMed

Affiliation: School of Biotechnology, Yeungnam University, Gyeongsan 712749, Republic of Korea.

ABSTRACT
Glucagon receptor (GCGR) is a secretin-like (class B) family of G-protein coupled receptors (GPCRs) in humans that plays an important role in elevating the glucose concentration in blood and has thus become one of the promising therapeutic targets for treatment of type 2 diabetes mellitus. GCGR based inhibitors for the treatment of type 2 diabetes are either glucagon neutralizers or small molecular antagonists. Management of diabetes without any side effects is still a challenge to the medical system, and the search for a new and effective natural GCGR antagonist is an important area for the treatment of type 2 diabetes. In the present study, a number of natural compounds containing antidiabetic properties were selected from the literature and their binding potential against GCGR was determined using molecular docking and other in silico approaches. Among all selected natural compounds, curcumin was found to be the most effective compound against GCGR followed by amorfrutin 1 and 4-hydroxyderricin. These compounds were rescored to confirm the accuracy of binding using another scoring function (x-score). The final conclusions were drawn based on the results obtained from the GOLD and x-score. Further experiments were conducted to identify the atomic level interactions of selected compounds with GCGR.

No MeSH data available.


Related in: MedlinePlus