In silico investigation of thiazole–semicarbazide hybrids as dual GSK-3β/Tau inhibitors for Alzheimer’s disease

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 by application of structure-based scaffold hopping and molecular hybridization strategies. Molecular docking was carried out on Glide module; Molecular dynamics simulation of 500 ns was executed employing Desmond and ADMET prediction was achieved by QikProp modules of Schrödinger. Through molecular docking studies targeting the GSK-3β and Tau enzymes, the compounds DVK5 and DVK11 were identified as promising inhibitors, showing favorable interactions within the active sites of these proteins, with docking energies of − 9.863 and – 8.994 kcal/mol , respectively. Molecular dynamics simulations further revealed that the DVK5 and DVK11 complexes exhibited stable interactions within the active sites of GSK-3β and Tau throughout a 500 ns simulation. Additionally, in silico ADMET analysis demonstrated that DVK10 exhibited an excellent human oral absorption rate of 75.175% , outperforming other compounds in the series. These findings strongly suggest the potential of DVK5 and DVK11 as dual inhibitors of GSK-3β and Tau, offering a basis for future drug development studies for the development of new lead compounds for AD treatment.