Structure-Based Drug Design: Identification of Glucokinase Activators from Natural Compounds for the Treatment of 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.

Automated summary

Glucokinase Activators (GKA) are small molecules that can bind to GK allosterically and effectively reduce plasma blood glucose levels, making them a potential therapeutic target for treating type 2 diabetes (T2D). In this study, a structure-based virtual screening was conducted on compounds from the Universal Natural Product Database (UNPD), resulting in the identification of four potential GKA small molecules. These compounds were found to interact strongly with specific active site residues of GK and satisfy drug-likeness criteria. Molecular dynamics simulation further confirmed the stability of the enzyme-small molecule complexes. Overall, this study provides valuable insights for identifying novel small molecules as GKAs.