QSAR Models for Prediction of Glycogen Synthase Kinase-3β Inhibitory Activity of Indirubin Derivatives

Glycogen Synthase (GS) Kinase‐3 (GSK‐3), a serine/threonine kinase, isolated and purified as an enzyme capable of phosphorylating and inactivating the enzyme GS is a fascinating enzyme with diverse biological actions in intracellular signaling pathways. A large body of evidence supports speculation that pharmacological inhibitors of GSK‐3 could be used to treat several disorders including Alzheimer's disease and other neurodegenerative diseases, bipolar affective disorder, diabetes, various types of cancer, and diseases caused by unicellular parasites that express GSK‐3 homologues. In the present work, we have carried out a Quantitative Structure–Activity Relationship (QSAR) study on indirubin derivatives reported as potent GSK‐3β inhibitors using molecular descriptors calculated by CODESSA and Molconn‐Z. Also a novel Three‐Dimensional QSAR (3D‐QSAR) study based on the principle of the alignment of pharmacophoric features by PHASE module of Schrödinger suite has been carried out on the same set of inhibitors. Statistically significant 2‐D (R2=0.93) and 3‐D (R2=0.97) QSAR models were generated using 36 molecules in the training set. The predictive ability of both models was determined using a randomly chosen test set of eight molecules which gave predictive correlation coefficients ($\rm{ R_{{\rm{pred}}}^{\rm{2}} }$) of 0.6 and 0.91, respectively for 2‐D and 3‐D models, indicating good predictive power. The cocrystallographic data of GSK‐3β with indirubin‐3′‐monoxime ligand allowed us to compare the PHASE pharmacophore model with experimental intermolecular interactions. The results of PHASE pharmacophore hypothesis AADDRR correspond very closely to the interactions recorded in the active site of the ligand bound complex. This relation between the crystallographic data and pharmacophore hypothesis allowed us to confirm the preferential binding mode of indirubins inside the active site. These studies showed that 3D‐QSAR model is a better predictive model for the indirubins compared to 2D‐QSAR model.