Ligand-based modeling followed by in vitro bioassay yielded new potent glucokinase activators

•30 Glucokinase activators were modeled by a combination of pharmacophore and QSAR analyses.•The resulting models were validated by ROC curve and against an external list of compounds.•The optimal models were used as 3D search query against the NCI list of compounds.•Hits exhibited significant bioactivation of glucokinase at 10 μM.

Glucokinase (GK) has received recent interest as a valid antidiabetic target. With this in mind, we applied a computational workflow based on combining pharmacophore modeling and QSAR analysis followed by in silico screening toward the discovery of novel GK activators. Virtual screening identified 10 promising bioactivators from the National Cancer Institute (NCI) list of compounds. The most potent NCI hit illustrated 6.3-fold GK activation at 10 μM. These results demonstrated that our virtual screening protocol was able to identify novel GK activator leads for subsequent development into potential antidiabetic agents.

Graphical abstractPharmacophore/QSAR modelling accessed new potent glucokinase activators.Figure optionsDownload full-size imageDownload high-quality image (191 K)Download as PowerPoint slide