Exploring novel and potent glycogen synthase kinase-3β inhibitors through systematic drug designing approach.

Significant implications of glycogen synthase kinase-3β (GSK-3β) have been reported in various neuronal disorders and malignant cancers. GSK-3β modulates diverse protein targets through phosphorylation, and its aberrant activity leads to neurological complications as well as tumour onset. Therefore, inhibiting GSK-3β activity through active-site fitting molecules may offer a favourable strategy for intercepting these disorders. This comprehensive study used multiple assays in tandem in order to explore the most potent GSK-3β inhibitor. Following structural similarity screening, 135 molecular docking and 135 standard MM-GBSA experiments were performed using AZD1080, a known inhibitor as standard. Among the 32 molecules demonstrating a stronger binding affinity than reference, only the two most potent molecules were chosen and their binding free energy was compared to AZD1080 using the Desmond trajectory clustering and eventual MM-GBSA. Additionally, the interaction status of these molecules and AZD1080 with GSK-3β was explored post-molecular dynamics. The stability of the strongest molecule (most potent) was evaluated in the active site of the above-mentioned kinase keeping its apo-form as reference. Notably, the e-Pharmacophores mapping was performed to address the level of complementarity of the most potent molecule and AZD1080 with the functional site of GSK-3β. Using various techniques, we identified the molecule with PubChem CID: 11167509 as the strongest molecule for obstructing GSK-3β, which may serve as a promising therapeutic after the meticulous evaluation on diverse models.