Identification of new GSK3β inhibitors through a consensus machine learning-based virtual screening

Glycogen synthase kinase-3 beta (GSK3β) is a serine/threonine kinase that plays key roles in glycogen metabolism, Wnt/β-catenin signaling cascade, synaptic modulation, and multiple autophagy-related signaling pathways. GSK3β is an attractive target for drug discovery since its aberrant activity is involved in the development of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. In the present study, multiple machine learning models aimed at identifying novel GSK3β inhibitors were developed and evaluated for their predictive reliability. The most powerful models were combined in a consensus approach, which was used to screen about 2 million commercial compounds. Our consensus machine learning-based virtual screening led to the identification of compounds G1 and G4, which showed inhibitory activity against GSK3β in the low-micromolar and sub-micromolar range, respectively. These results demonstrated the reliability of our virtual screening approach. Moreover, docking and molecular dynamics simulation studies were employed for predicting reliable binding modes for G1 and G4, which represent two valuable starting points for future hit-to-lead and lead optimization studies.