Last update 01 Nov 2024

GK x GKRP

Last update 01 Nov 2024

Basic Info

Related Targets

GKGKRP

Drugs associated with GK x GKRP

AMG-1694

Target

GK x GKRP

Mechanism

GK modulators [+1]

Active Org.-

Originator Org.

Amgen, Inc.

Active Indication-

Inactive Indication

Diabetes Mellitus

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

AMG-3969

Target

GK x GKRP

Mechanism

GK modulators [+1]

Active Org.-

Originator Org.

Nanjing Anjin Pharmaceutical Co., Ltd.

Active Indication-

Inactive Indication

Diabetes Mellitus

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with GK x GKRP

100 Translational Medicine associated with GK x GKRP

0 Patents (Medical) associated with GK x GKRP

Literatures (Medical) associated with GK x GKRP

01 Apr 2024·Biotechnology and Applied Biochemistry

Tetrahydropalmatine from medicinal plants activates human glucokinase to regulate glucose homeostasis

Article

Author: Singh, Sweta ; Bhargava, Shobha ; Sharma, Shilpy ; Kumar, Ameeta Ravi ; Ghosh, Payel

AbstractMany synthetic glucokinase activators (GKAs), modulating glucokinase (GK), an important therapeutic target in diabetes have failed to clear clinical trials. In this study, an in silico structural similarity search with differing scaffolds of reference GKAs have been used to identify derivatives from natural product databases. Ten molecules with good binding score and similar interactions to that in the co‐crystallized GK as well good activation against recombinant human GK experimentally were identified. Tetrahydropalmatine, an alkaloid present in formulations and drugs from medicinal plants, has not been explored as an antidiabetic agent and no information regarding its mechanism of action or GK activation exists. Tetrahydropalmatine activates GK with EC50 value of 71.7 ± 17.9 μM while lowering the S0.5 (7.1 mM) and increasing Vmax (9.22 μM/min) as compared to control without activator (S0.5 = 10.37 mM; Vmax = 4.8 μM/min). Kinetic data (α and β values) suggests it to act as mixed, nonessential type activator. Using microscale thermophoresis, Kd values of 3.8 μM suggests a good affinity for GK. In HepG2 cell line, the compound potentiated the uptake of glucose and maintained glucose homeostasis by increasing the expression of GK, glycogen synthase, and insulin receptor genes and lowering the expression of glucokinase regulatory protein (GKRP) and glucagon. Tetrahydropalmatine at low concentrations could elicit a good response by reducing expression of GKRP, increasing expression of GK while also activating it. Thus, it could be used alone or in combination as therapeutic drug as it could effectively modulate GK and alter glucose homeostasis.

01 Jan 2023·PloS one

Molecular insights into the inhibitory potential of anthocyanidins on glucokinase regulatory protein.

Article

Author: Kenneth, Christian ; Anugrah, Daru Seto Bagus ; Junedi, Sendy ; Julianus, Jeffry

Computational methods were used to investigate six anthocyanidins exhibiting antidiabetic activity by inhibiting glucokinase regulatory protein (GKRP) activity. Density functional theory was used to optimise the geometry of anthocyanidins and calculate their quantum chemical properties. A blind docking method was employed to conduct a molecular docking study, which revealed that delphinidin (Del), cyanidin (Cya), and pelargonidin (Pel) as potential GKRP inhibitors with the lowest binding free energy of -8.7, -8.6, and -8.6 kcal/mol, corresponding to high binding affinity. The molecular dynamics study further verified the blind docking results by showing high GKRP-F1P complex stability and high binding affinity calculated through the MM/GBSA method, upon the binding of pelargonidin. The lower RMSF values of pivotal GK-interacting residues for GKRP-F1P-Pel compared to GKRP-F1P, as a positive control, indicating pelargonidin ability to maintain the inactive conformation of GKRP through the inhibition of GK binding. The key residues that control the binding of the F1P to GKRP and anthocyanidin to GKRP-F1P were also identified in this study. Altogether, pelargonidin is anthocyanidins-derived natural products that have the most potential to act as inhibitors of GKRP and as antidiabetic nutraceuticals.

01 Jan 2023·Frontiers in endocrinology

Glucokinase regulatory protein: a balancing act between glucose and lipid metabolism in NAFLD.

Review

Author: Ji, Guang ; Zhang, Ziqi ; Li, Meng

Non-alcoholic fatty liver disease (NAFLD) is a common liver disease worldwide, affected by both genetics and environment. Type 2 diabetes (T2D) stands as an independent environmental risk factor that precipitates the onset of hepatic steatosis and accelerates its progression to severe stages of liver damage. Furthermore, the coexistence of T2D and NAFLD magnifies the risk of cardiovascular disease synergistically. However, the association between genetic susceptibility and metabolic risk factors in NAFLD remains incompletely understood. The glucokinase regulator gene (GCKR), responsible for encoding the glucokinase regulatory protein (GKRP), acts as a regulator and protector of the glucose-metabolizing enzyme glucokinase (GK) in the liver. Two common variants (rs1260326 and rs780094) within the GCKR gene have been associated with a lower risk for T2D but a higher risk for NAFLD. Recent studies underscore that T2D presence significantly amplifies the effect of the GCKR gene, thereby increasing the risk of NASH and fibrosis in NAFLD patients. In this review, we focus on the critical roles of GKRP in T2D and NAFLD, drawing upon insights from genetic and biological studies. Notably, prior attempts at drug development targeting GK with glucokinase activators (GKAs) have shown potential risks of augmented plasma triglycerides or NAFLD. Conversely, overexpression of GKRP in diabetic rats improved glucose tolerance without causing NAFLD, suggesting the crucial regulatory role of GKRP in maintaining hepatic glucose and lipid metabolism balance. Collectively, this review sheds new light on the complex interaction between genes and environment in NAFLD, focusing on the GCKR gene. By integrating evidence from genetics, biology, and drug development, we reassess the therapeutic potential of targeting GK or GKRP for metabolic disease treatment. Emerging evidence suggests that selectively activating GK or enhancing GK-GKRP binding may represent a holistic strategy for restoring glucose and lipid metabolic balance.

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