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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

A. Binding mode of ligand 5. B. Binding mode of ligand 7. Ligands are shown in ball and stick display. Amino acids are shown in line view.
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Figure 6: A. Binding mode of ligand 5. B. Binding mode of ligand 7. Ligands are shown in ball and stick display. Amino acids are shown in line view.

Mentions: The three cyclic moieties joined in Y shape contain amide linkage along the stem of the Y, the amide NH acts as hydrogen bond donor and involved in specific hydrogen bond formation with Arg63 backbone carbonyl O. Heterocyclic group containing N at position two connected to the amide NH of ligand makes another specific hydrogen bond formation with the Arg63 backbone NH (Fig. 4). This class of ligands contains cyclopentyl or cyclohexyl (R3) as one arm of the ligand and shows packing in hydrophobic pocket 3 (Fig. 6A). R3 group nestles between two Met210, Met235 and Tyr214 side chain at allosteric site. Fig. (4) shows binding interactions of ligand 1 (class I GKA). Ligands containing hydrogen bond acceptor group in R2 makes additional hydrogen bond formation with Tyr215 and Gln98. Aligned binding modes of class I ligands are shown in Fig. (5). Ligand 3 shows three hydrogen bond formations with Arg63 due to presence of ester group in thiazole ring. Val62, Pro66, Ile159, Met210, Ile211, Tyr214, Met235, Cys220, Val452, Val455, Ala456 are the main residues involved in hydrophobic interactions with this class of ligands.


Comparative docking assessment of glucokinase interactions with its allosteric activators.

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

A. Binding mode of ligand 5. B. Binding mode of ligand 7. Ligands are shown in ball and stick display. Amino acids are shown in line view.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: A. Binding mode of ligand 5. B. Binding mode of ligand 7. Ligands are shown in ball and stick display. Amino acids are shown in line view.
Mentions: The three cyclic moieties joined in Y shape contain amide linkage along the stem of the Y, the amide NH acts as hydrogen bond donor and involved in specific hydrogen bond formation with Arg63 backbone carbonyl O. Heterocyclic group containing N at position two connected to the amide NH of ligand makes another specific hydrogen bond formation with the Arg63 backbone NH (Fig. 4). This class of ligands contains cyclopentyl or cyclohexyl (R3) as one arm of the ligand and shows packing in hydrophobic pocket 3 (Fig. 6A). R3 group nestles between two Met210, Met235 and Tyr214 side chain at allosteric site. Fig. (4) shows binding interactions of ligand 1 (class I GKA). Ligands containing hydrogen bond acceptor group in R2 makes additional hydrogen bond formation with Tyr215 and Gln98. Aligned binding modes of class I ligands are shown in Fig. (5). Ligand 3 shows three hydrogen bond formations with Arg63 due to presence of ester group in thiazole ring. Val62, Pro66, Ile159, Met210, Ile211, Tyr214, Met235, Cys220, Val452, Val455, Ala456 are the main residues involved in hydrophobic interactions with this class of ligands.

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