Identification of novel ligands against GSK-3β: Molecular docking, ADMET filtering, MD simulations, MM-GBSA studies,...

Glycogen synthase kinase-3β (GSK-3β) is a key enzyme involved in tau hyperphosphorylation, a key pathological mechanism leading to tau aggregation and thus, Alzheimer's disease. It also has a significant role in neuroinflammation, induction of BACE1, and amyloid-β aggregation. Such crucial pathological events are involved intricately with the Alzheimer's disease pathophysiology which makes this enzyme an attractive drug target. Designing a competitive ATP-site inhibitor of GSK-3β is the approach adopted here in an attempt to target tau pathology. Tetrazole is selected as a scaffold taking into account the previously reported inhibitors bearing nitrogen heterocycles which are at the heart of drug design strategies. A library of disubstituted tetrazole analogs was designed and molecular docking was performed. The top 30 molecules were then passed through several ADMET filters with a special preference given to BBB permeability. The hit molecules obtained after this were analyzed for their amino acid interactions. The docked complexes were used to perform MD simulations for 100 ns and later MM-GBSA studies were performed with staurosporine and co-crystallized ligand as reference molecules. Furthermore, various chemical reactivity parameters and the HOMO-LUMO energy gap were analyzed with DFT studies using B3LYP functional. The best molecule obtained was TD30, revealing a docking score of -167.036, an average RMSD of 2.15 Å for 100 ns simulation time, average ΔG_Binding energy of -86.55 ± 4.45 kcal/mol, and an HOMO-LUMO energy gap of 4.044 eV; all corroborating the potential of TD30 for future research and enzyme inhibition assays.