Insight into glycogen synthase kinase-3β inhibitory activity of phyto-constituents from Melissa officinalis: in silico studies.

Over activity of Glycogen synthase kinase-3β (GSK-3β), a serine/threonine-protein kinase has been implicated in a number of diseases including stroke, type II diabetes and Alzheimer disease (AD). This study aimed to find novel inhibitors of GSK-3β from phyto-constituents of Melissa officinalis with the aid of computational analysis. Molecular docking, induced-fit docking (IFD), calculation of binding free energy via the MM-GBSA approach and Lipinski's rule of five (RO5) were employed to filter the compounds and determine their druggability. Most importantly, the compounds pIC50 were predicted by machine learning-based model generated by AutoQSAR algorithm. The generated model was validated to affirm its predictive model. The best model obtained was Model kpls_desc_38 (R2 = 0.8467 and Q2 = 0.8069), and this external validated model was utilized to predict the bioactivities of the lead compounds. While a number of characterized compounds from Melissa officinalis showed better docking score, binding free energy alongside adherence to RO5 than co-cystallized ligand, only three compounds (salvianolic acid C, ellagic acid and naringenin) showed more satisfactory pIC50. The results obtained in this study can be useful to design potent inhibitors of GSK-3β.