Discovery of novel and highly potential inhibitors of glycogen synthase kinase 3-beta (GSK-3β) through structure-based pharmacophore modeling, virtual computational screening, docking and in silico ADMET analysis.

The protein Glycogen Synthase Kinase 3-Beta (GSK-3β), is a promising therapeutic target for treating various diseases such as neurodegenerative disorders, diabetes, inflammation and cancer. This study aims to investigate the potential of compounds targeting inflammation or carbohydrate metabolism to selectively inhibit GSK3β by binding to its ATP site. To achieve this goal, we filtered a database of 49367 molecules involved in carbohydrate metabolism or targeting inflammation using various computational analyses, including pharmacophore modeling, molecular docking, dynamic simulation, prime MM-GBSA calculation, and in silico ADME studies. We generated a pharmacophore model (hypo S: AADDHRR) using two different crystallographic complexes of GSK3β and evaluated the model's performance in identifying hits using various parameters, including EF, GH, ROC, AUC and BEDROC. Subsequently, we performed various dockings (HTVS, SP, XP and IFD) for the retrieved hits and found that, 5 out of the top 10 ranked compounds had the scaffold of pyrazolidine 3,5-dione, which has never been reported to inhibit kinases. We also conducted ADMET studies to and concluded that compound N6 exhibited the best pharmacokinetic profile passing the blood-brain barrier, possessing high lipophilicity and a high coefficient of skin permeability in the intestines, along with good bioavailability and low toxicity risk assessment. Dynamic simulation were also performed indicating that compounds N6 derived from pyrazolidine 3,5-dione demonstrated better binding potential for GSK3β during the simulation period. Therefore, we propose that compounds derived from pyrazolidine-3,5-dione, which modulate the activity of lysosomal alpha-glucosidase could serve as a novel scaffold for the selective inhibition of GSK-3β.Communicated by Ramaswamy H. Sarma.