Identification of Phytochemicals as Promising GSK-3β Inhibitors for Cancer Therapeutic Potential Through Virtual Screening, Molecular Docking, MD Simulation and MM-PBSA Calculation

The serine/threonine (S/T) protein kinase glycogen synthase kinase-3 (GSK-3[Formula: see text] has been identified as a new target for anticancer medications. Although GSK-3[Formula: see text] is involved in multiple pathways linked to the etiology of various cancers, no specific GSK-3[Formula: see text] inhibitor has been authorized for cancer therapy. Most of its inhibitors have toxicity effects, therefore, there is a need to develop safe and more potent inhibitors. Despite previous studies, this study used compounds to inhibit GSK-3[Formula: see text] that had not previously been considered. To find viable options for targeting the GSK-3[Formula: see text] binding pocket, natural anticancer drugs were rigorously computationally screened in this work. Docking-based virtual screening, physicochemical and ADMET analysis and molecular dynamics (MD) simulations were among the steps in the screening procedure. Ultimately, four substances were found to have significant binding affinities to GSK-3[Formula: see text]: Diosmin, Linarin, epigallocatechin gallate (EGCG) and 7,8-dihydroxyflavone (DHF). The binding affinities of Diosmin and Linarin were −9.6 kcal/mol and −9.6 kcal/mol, respectively, higher than the ATP-positive control (−8.2 kcal/mol). However, the compounds’ interaction with GSK-3[Formula: see text] was optimized using MD simulations for 300 ns. The simulations revealed that Diosmin was more stable and consistent throughout the investigation than other interacting chemicals. It was also expected that these hits would have good drug-like qualities. Ultimately, these data suggest that Diosmin may undergo experimental validation to assess its potential as a cancer treatment.