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Last update 08 May 2025

GK

Last update 08 May 2025

Basic Info

Synonyms

ATP:glycerol 3-phosphotransferase, GK, GK1

+ [3]

Introduction

Kinase that plays a key role in glycerol metabolism, catalyzing its phosphorylation to produce sn-glycerol 3-phosphate. Sn-glycerol 3-phosphate is a crucial intermediate in various metabolic pathways, such as the synthesis of glycerolipids and triglycerides, glycogenesis, glycolysis and gluconeogenesis.

Drugs associated with GK

Glycerol analogue 3(University of St Andrews)

Target

Mechanism

GK inhibitors

Active Org.

University of St. Andrews

Originator Org.

University of St. Andrews

Active Indication

Trypanosomiasis

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Glycerol analogue 4(University of St Andrews)

Target

Mechanism

GK inhibitors

Active Org.

University of St. Andrews

Originator Org.

University of St. Andrews

Active Indication

Trypanosomiasis

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Glycerol analogue 5(University of St Andrews)

Target

Mechanism

GK inhibitors

Active Org.

University of St. Andrews

Originator Org.

University of St. Andrews

Active Indication

Trypanosomiasis

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with GK

100 Translational Medicine associated with GK

0 Patents (Medical) associated with GK

2,445

Literatures (Medical) associated with GK

01 Dec 2025·Journal of Computer-Aided Molecular Design

In silico design of dehydrophenylalanine containing peptide activators of glucokinase using pharmacophore modelling, molecular dynamics and machine learning: implications in type 2 diabetes

Article

Author: Lynn, Andrew ; Rana, Swati ; Singh, Sohini ; Yadav, Siddharth ; Mathur, Puniti ; Manish, Manish

Diabetes represents a significant global health challenge associated with substantial healthcare costs and therapeutic complexities. Current diabetes therapies often entail adverse effects, necessitating the exploration of novel agents. Glucokinase (GK), a key enzyme in glucose homeostasis, primarily regulates blood glucose levels in hepatocytes and pancreatic cells. Unlike other hexokinases, GK exhibits unique kinetic properties, such as a high Km and lack of feedback inhibition, allowing it to function as a glucose sensor Glucokinase activators (GKAs) have emerged as promising candidates for managing type-2 diabetes by allosterically enhancing GK activity. Despite initial promise, existing GKAs face significant safety concerns, driving the need for compounds with improved safety profiles. This study introduces a novel chemical scaffold within the GKA landscape: peptide-based GKAs incorporating non-standard amino acid residues such as α,β-dehydrophenylalanine (ΔPhe/ΔF). A virtual library containing 3,368,000 peptides was constructed and screened using a hybrid pharmacophore, namely DHRR (D: donor; H: hydrogen; R: aromatic ring). Molecular docking and molecular dynamics simulations assisted in identifying three peptides, Pep-11, Pep-15, and Pep-16, which depicted stable binding at the allosteric site of Glucokinase. These peptides were synthesized using a combination of solid and solution phase synthesis methods. In vitro enzymatic activity of glucokinase was increased by at least 1.5 times in the presence of these peptides. Several machine learning algorithms were explored as alternatives to conventional in-silico methods for predicting GK activity. Regression and tree-based algorithms outperformed other methods, with the logistic regression and random forest classifiers both achieving an ROC-AUC of 0.98.

01 Jul 2025·Bioorganic & Medicinal Chemistry Letters

Discovery of liver-selective glucokinase activators comprising N-(4-alkylthiazol-2-yl)benzamides and N-(3-alkyl-1,2,4-thiadiazol-5-yl)benzamides for the treatment of metabolic disorders

Article

Author: Mathur, Arvind ; Kalinowski, Stephen ; Spronk, Steven A ; Brigance, Robert P ; Zalaznick, Jacob ; Janovitz, Evan B ; Kirby, Mark ; Catanio, Helen Grace ; Shi, Yan ; Marathe, Punit ; Xu, Carrie ; Wang, Ying ; Yoon, David S ; Yang, Yanou ; Taylor, Joseph ; Barrish, Joel C ; Behnia, Kamelia ; Wu, Shung ; Zhang, Hao ; Kopcho, Lisa M ; Tao, Shiwei ; Josephs, Jonathan ; Zebo, Rachel ; Chen, Sean S ; Whaley, Jean ; Smirk, Rebecca A ; Meng, Wei ; Cheng, Peter T W ; Zinker, Bradley

Glucokinase ("GK") plays a critical role in regulating glucose homeostasis within the body. Proof-of-concept animal models demonstrated that small molecule GK activation enhances glucose uptake and utilization by various tissues, including liver and pancreas. Accordingly, glucokinase activators ("GKAs") were extensively explored as a potential therapy for carbohydrate metabolism disorders. Yet in clinical trials, mechanism-based hypoglycemia was often observed when GK was activated in both liver and pancreas. One ameliorative approach was to pursue hepatocentric GKAs. Described herein is a series of liver selective GKAs based on N-(4-alkylthiazol-2-yl)benzamide and N-(3-alkyl-1,2,4-thiadiazol-5-yl)benzamide pharmacophores. Optimization efforts revealed that enhanced liver selectivity could be achieved by replacing diethylphosphonate group (compound 1) with a dimethylphosphinate (compound 3). Due to mutagenicity of a putative aminoheterocycle metabolite of 3, subsequent amines were triaged using SOS chromotest. Efforts ultimately led to identification of thiazole-based compounds 11-13, which exhibited significant glucose lowering in acute DIO ("diet-induced obese") mouse OGTT ("oral glucose tolerance test") studies. However, insulin secretion was observed at higher doses, and thus the desired therapeutic window between efficacy and insulin secretion was not achieved. Thiadiazole-based compounds were then explored to assess whether this modification could obviate the insulin secretion observed with the thiazole series. Several thiadiazoles were discovered with exceptionally high liver selectivity and drug liver concentrations when evaluated in mouse pharmacokinetic studies. Compounds 17-19 and 20-22 were advanced into acute DIO OGTT studies, but were inactive. Notably, a relatively higher degree of plasma protein binding was observed for the non-efficacious vs. efficacious compounds.

01 Jun 2025·Fitoterapia

Molecular events responsible for hypoglycaemic attributes of Fernandoa adenophylla extract in streptozotocin-induced diabetes

Article

Author: Muhammad, Taha ; Al Musayeib, Nawal M ; Hakeem, Ammara ; Saleem, Mohammad ; Anwar, Rukhsana ; Ebada, Sherif S ; Ashour, Mohamed L ; Asif, Muhammad

Traditionally, people use the decoction of Fernandoa adenophylla leaves to treat diabetes mellitus. This study investigated the antidiabetic activity of F. adenophylla methanol extract (Fa.Me) in streptozotocin (STZ)-induced diabetes rats, with metformin as a positive control. We analysed several relevant biomarkers and antioxidant enzymes using ELISA assays and assessed gene expression (PEPCK, G6-PDH, PFKFB1, GS, GK, and GLUT-4) using qRT-PCR. The obtained results revealed an upregulation of G6-PDH (PPS pathway), PFKFB1 (glycolysis), GS (glycogenesis), and GLUT-4 (glucose transporter), while the PEPCK (gluconeogenesis) gene was downregulated. Besides, the antidiabetic biomarkers showed elevated adiponectin, SOD, and glutathione levels; however, amylase level decreased in the treatment groups. We observed a dose-dependent reduction in HbA1c, insulin, and random blood glucose in the metformin and Fa.Me groups. Histopathological analysis of animals' liver and pancreas showed an intact structure of hepatocytes in extract groups, while atrophic changes in the pancreas were observed in the diseased group. By modulating the oxidative stress and glucose metabolism-control genes, F. adenophylla demonstrated significant antidiabetic properties and held potential for further clinical exploration.

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