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Comparative docking assessment of glucokinase interactions with its allosteric activators.

Kumari V, Li C - Curr Chem Genomics (2008)

Bottom Line: Our dockings have overall consistency with experimental data in both docking modes and simulated binding free energies, and offer insights on understanding GK/GKA interactions and further GKA design.Specifically, for the first pocket, involvement of Arg63 as key residue in two specific hydrogen-bond formations with all allosteric activators defines the binding feature; for the second pocket, it has the most diverse binding interactions, mostly aromatic, hydrophobic and multiple hydrogen bonds.The site has the best potential for further GKA optimization by utilizing aromatic heterocycles and hydrogen bond forming linkers to build the GKA 2(nd) arm.

View Article: PubMed Central - PubMed

Affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 500 West 12th Ave., Columbus, OH 43210, USA.

ABSTRACT
Glucokinase (GK) is expressed in multiple organs and plays a key role in hepatic glucose metabolism and pancreatic insulin secretion. GK could indeed serve as pacemaker of glycolysis and could be an attractive target for type 2 diabetes (T2D). The recent preclinical data of first GK activator RO-28-1675 has opened up a new field of GK activation as a powerful tool in T2D therapies. The GK allosteric site is located ~20A away from glucose binding site. Chemical structure of Glucokinase activators (GKA) includes three chemical arms; all consisting of cyclic moiety and joined in a shape resembling the letter Y. In this study, comparative docking assessment using Autodock4 revealed that the three arms bind to three aromatic/hydrophobic subpockets at the allosteric site. Our dockings have overall consistency with experimental data in both docking modes and simulated binding free energies, and offer insights on understanding GK/GKA interactions and further GKA design. Specifically, for the first pocket, involvement of Arg63 as key residue in two specific hydrogen-bond formations with all allosteric activators defines the binding feature; for the second pocket, it has the most diverse binding interactions, mostly aromatic, hydrophobic and multiple hydrogen bonds. The site has the best potential for further GKA optimization by utilizing aromatic heterocycles and hydrogen bond forming linkers to build the GKA 2(nd) arm.

No MeSH data available.


Related in: MedlinePlus

Binding interactions of ligand 18 (A). Hydrogen bond formation with Arg63 amino acid (B, C).
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Figure 10: Binding interactions of ligand 18 (A). Hydrogen bond formation with Arg63 amino acid (B, C).

Mentions: This class of GKAs contains ligands which have some unique groups. Ligand 19 and 20 contains cyclopropyl group connecting three arms. Docking studies of ligand19 shows comparable binding energy to the experimental value. Clustering of docked conformations also gave high confidence, 95% of the docked conformations fall in one cluster with 1.5 Å RMSD tolerance. Docking mode and clustering histogram of ligand 19 are shown in Fig. (9). Thr65 is involved in hydrogen bond formation with O of methyl sulfone group. Ligand 18 does not contain amide group, this is structurally different from all other ligands. Docking studies of this ligand also shows involvement of Arg63 in two specific hydrogen bond formation with N of pyridine and carbonyl group of carboxylic group of ligand 18 (Fig. 10). This suggests that Arg63 is highly conserved residue which is specifically involved in hydrogen bond formation with GKAs. Hydrophobic interactions for this class were similar to that of other classes of GKAs.


Comparative docking assessment of glucokinase interactions with its allosteric activators.

Kumari V, Li C - Curr Chem Genomics (2008)

Binding interactions of ligand 18 (A). Hydrogen bond formation with Arg63 amino acid (B, C).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2803441&req=5

Figure 10: Binding interactions of ligand 18 (A). Hydrogen bond formation with Arg63 amino acid (B, C).
Mentions: This class of GKAs contains ligands which have some unique groups. Ligand 19 and 20 contains cyclopropyl group connecting three arms. Docking studies of ligand19 shows comparable binding energy to the experimental value. Clustering of docked conformations also gave high confidence, 95% of the docked conformations fall in one cluster with 1.5 Å RMSD tolerance. Docking mode and clustering histogram of ligand 19 are shown in Fig. (9). Thr65 is involved in hydrogen bond formation with O of methyl sulfone group. Ligand 18 does not contain amide group, this is structurally different from all other ligands. Docking studies of this ligand also shows involvement of Arg63 in two specific hydrogen bond formation with N of pyridine and carbonyl group of carboxylic group of ligand 18 (Fig. 10). This suggests that Arg63 is highly conserved residue which is specifically involved in hydrogen bond formation with GKAs. Hydrophobic interactions for this class were similar to that of other classes of GKAs.

Bottom Line: Our dockings have overall consistency with experimental data in both docking modes and simulated binding free energies, and offer insights on understanding GK/GKA interactions and further GKA design.Specifically, for the first pocket, involvement of Arg63 as key residue in two specific hydrogen-bond formations with all allosteric activators defines the binding feature; for the second pocket, it has the most diverse binding interactions, mostly aromatic, hydrophobic and multiple hydrogen bonds.The site has the best potential for further GKA optimization by utilizing aromatic heterocycles and hydrogen bond forming linkers to build the GKA 2(nd) arm.

View Article: PubMed Central - PubMed

Affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 500 West 12th Ave., Columbus, OH 43210, USA.

ABSTRACT
Glucokinase (GK) is expressed in multiple organs and plays a key role in hepatic glucose metabolism and pancreatic insulin secretion. GK could indeed serve as pacemaker of glycolysis and could be an attractive target for type 2 diabetes (T2D). The recent preclinical data of first GK activator RO-28-1675 has opened up a new field of GK activation as a powerful tool in T2D therapies. The GK allosteric site is located ~20A away from glucose binding site. Chemical structure of Glucokinase activators (GKA) includes three chemical arms; all consisting of cyclic moiety and joined in a shape resembling the letter Y. In this study, comparative docking assessment using Autodock4 revealed that the three arms bind to three aromatic/hydrophobic subpockets at the allosteric site. Our dockings have overall consistency with experimental data in both docking modes and simulated binding free energies, and offer insights on understanding GK/GKA interactions and further GKA design. Specifically, for the first pocket, involvement of Arg63 as key residue in two specific hydrogen-bond formations with all allosteric activators defines the binding feature; for the second pocket, it has the most diverse binding interactions, mostly aromatic, hydrophobic and multiple hydrogen bonds. The site has the best potential for further GKA optimization by utilizing aromatic heterocycles and hydrogen bond forming linkers to build the GKA 2(nd) arm.

No MeSH data available.


Related in: MedlinePlus