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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. [ABSTRACT FROM AUTHOR]

The fundamental of molecular modeling is the interaction and binding to form a complex, because it explains the action of most drugs to a receptor active site. In the present study, different semiempirical ( RM1, AM1, PM3, MNDO) and ab intio ( HF, DFT) charge models were investigated for their performance in prediction of docking pose against CDK2 proteins with their respective inhibitor. Further, multiple docking approaches and Prime/ MM- GBSA calculations were applied to predict the binding mode with respective charge model against CDK2 inhibitors. A reliable docking result was obtained using RRD, which showed significance improvement on ligand binding poses and docking score accuracy to the IFD. The combined use of RRD and Prime/ MM- GBSA method could give a high correlation between the predicted binding free energy and experimental biological activity. The preliminary results point out that AM1 could be a precious charge model for design of new drugs with enhanced success rate. As a very similar result was also found for a different system of the protein-ligand binding, the suggested scoring function based on AM1 method seems to be applicable in drug design. The results from this study can provide insights into highest success rate for design of potent and selective CDK2 inhibitors. [ABSTRACT FROM AUTHOR]