Glucokinase is a key enzyme which converts glucose into glucose-6-phosphate in the liver and pancreatic cells of the human. In the liver, glucokinase promotes the synthesis of glycogen, and in the pancreas, it helps in glucose-sensitive insulin release. It serves as a "glucose sensor" and thereby plays an important role in the regulation of glucose homeostasis. Due to this activity, glucokinase is considered as an attractive drug target for type 2 diabetes. It created a lot of interest among the researchers, and several small molecules were discovered. The research work was initiated in 1990. However, the hypoglycemic effect, increased liver burden, and loss of efficacy over time were faced during clinical development. Dorzagliatin, a novel glucokinase activator that acts on both the liver and pancreas, is in the latestage clinical development. TTP399, a promising hepatoselective GK activator, showed a clinically significant and sustained reduction in glycated hemoglobin with a low risk of adverse effects. The successful findings generated immense interest to continue further research in finding small molecule GK activators for the treatment of type 2 diabetes. The article covers different series of GK activators reported over the past decade and the structural insights into the GK-GK activator binding which, we believe will stimulate the discovery of novel GK activators to treat type 2 diabetes.

Glucokinase Activators (GKA) are novel small molecules that target GK and reduce plasma blood glucose by binding GK allosterically. It is considered as a potential therapeutic target to treat T2D. So, in an effort to identify compounds to treat T2D efficiently, a structure‐based virtual screening was performed on compounds from Universal Natural Product Database (UNPD) using FRED. Among 229358 compounds from UNPD, four compounds were identified as potential small molecules. The hit compounds UNPD 1354, UNPD 85595, UNPD 6604, and UNPD 88147 are found to interact strongly with active site residues ARG 63, VAL62, VAL452, TYR215, VAL 455, MET210, MET235, and TYR214. In addition, ADME predictions show that the compounds satisfy drug‐likeness criteria. Finally, the molecular dynamics simulation was carried out for 50 ns using the GROMACS 2020 package, the results confirm the stability of the enzyme‐HIT throughout the simulation time. Thus, this study may provide valuable insights into identifying novel small molecules as GKAs.