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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 mode of class II GKAs. A. Aligned binding mode of class II GKAs. B. Binding mode of ligand 9 at the allosteric site of GK, there is additional H bond formation between Arg63 side chain and the ligand.
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Figure 7: Binding mode of class II GKAs. A. Aligned binding mode of class II GKAs. B. Binding mode of ligand 9 at the allosteric site of GK, there is additional H bond formation between Arg63 side chain and the ligand.

Mentions: This class of GKAs lacks chiral carbon connected to amide group. Multi-substituted cyclic ring is present which acts as stem of Y letter and substituents on this ring orient in the shape of Y. Lack of chiral carbon center in these ligands makes ligands less flexible. Hydrophobic pocket 2 accommodates smaller hydrophobic groups while hydrophobic pocket 3 accommodates bigger hydrophobic groups. Fig. (7) shows binding mode of this class of ligands. This class also shows specific hydrogen bond formation with the Arg63 backbone. Ligands having carboxyl group attached to heterocyclic ring shows additional hydrogen bond formation with the Arg63 side chain and contributes to the binding energy. Tyr215 and Gln98 are involved in hydrogen bond formation with ether group. Amino group is present instead of ether group in ligand 10 and this amino group also shows hydrogen bond formation with Tyr215 and Gln98 amino acids. Crystal structure of ligand 10 bound at allosteric site of GK is present and our docking mode shows similar kind of binding interactions as crystal structure.


Comparative docking assessment of glucokinase interactions with its allosteric activators.

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

Binding mode of class II GKAs. A. Aligned binding mode of class II GKAs. B. Binding mode of ligand 9 at the allosteric site of GK, there is additional H bond formation between Arg63 side chain and the ligand.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Binding mode of class II GKAs. A. Aligned binding mode of class II GKAs. B. Binding mode of ligand 9 at the allosteric site of GK, there is additional H bond formation between Arg63 side chain and the ligand.
Mentions: This class of GKAs lacks chiral carbon connected to amide group. Multi-substituted cyclic ring is present which acts as stem of Y letter and substituents on this ring orient in the shape of Y. Lack of chiral carbon center in these ligands makes ligands less flexible. Hydrophobic pocket 2 accommodates smaller hydrophobic groups while hydrophobic pocket 3 accommodates bigger hydrophobic groups. Fig. (7) shows binding mode of this class of ligands. This class also shows specific hydrogen bond formation with the Arg63 backbone. Ligands having carboxyl group attached to heterocyclic ring shows additional hydrogen bond formation with the Arg63 side chain and contributes to the binding energy. Tyr215 and Gln98 are involved in hydrogen bond formation with ether group. Amino group is present instead of ether group in ligand 10 and this amino group also shows hydrogen bond formation with Tyr215 and Gln98 amino acids. Crystal structure of ligand 10 bound at allosteric site of GK is present and our docking mode shows similar kind of binding interactions as crystal structure.

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