Discovery of Novel Quinazoline Thiazole Uredio Analogs as Dual Inhibitors of GSK-3β and CK-1δ as Anti-Alzheimer’s Agents: Catching Two Fish with One Net

INTRODUCTION: AD is a widespread and debilitating neurodegenerative disorder, and existing treatments have demonstrated limited efficacy, emphasizing the need for novel therapeutic strategies. This study focused on the design of drug-like molecules with enhanced efficacy and minimized side effects through the application of structure-based scaffold hopping and molecular hybridization strategies. METHODS: Molecular docking was carried out on the Glide module, Molecular dynamics simulation of 500 ns was executed employing Desmond, and ADMET prediction was achieved by the QikProp modules of Schrodinger. RESULTS: Through molecular docking studies targeting the GSK-3β and CK-1δ enzymes, the compounds VDK12 and VDK14 were identified as promising inhibitors, showing favorable interactions within the active sites of these proteins, with docking energies of -9.9 kcal/mol and -10.1 kcal/mol, respectively. Molecular dynamics simulations further revealed that the VDK12 and VDK14 complexes exhibited stable interactions within the active sites of GSK-3β and CK-1δ throughout a 500 ns simulation. Additionally, in silico ADMET analysis demonstrated that VDK1 exhibited an excellent human oral absorption rate of 91.349%, outperforming other compounds in the series. DISCUSSION: Molecules as dual inhibitors were designed successfully by the application of scaffold hopping and molecular hybridization. Designed molecules demonstrated excellent molecular docking and dynamics simulation results with an appropriate ADMET profile. CONCLUSION: These findings strongly suggest the potential of VDK12 and VDK14 as dual inhibitors of GSK-3β and CK-1δ, offering a promising foundation for the development of new lead compounds for AD treatment.