Structure-Guided Design and In Silico Evaluation of Proteolysis-Targeting Chimeras (PROTACs) for the Selective Ubiquitin-Mediated Degradation of Glycogen Synthase Kinase-3 Beta (GSK-3β) as a Therapeutic Strategy in Alzheimer’s Disease

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder that is caused by a buildup of amyloid-beta plaques and neurofibrillary tau tangles in the brain. Glycogen synthase kinase-3 beta (GSK-3β) is an enzyme that contributes to tau phosphorylation and amyloid-beta production. There- fore, degrading this protein could be a potential therapeutic strategy targeting AD. Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules designed to mediate the selective degradation of target proteins (such as GSK-3β) by conjugating them to E3 ubiquitin ligases. This proximity-induced inter- action facilitates the ubiquitination of the target protein, leading to its subsequent degradation by the ubiquitin-proteasome system. We hypothesize that PROTAC P1 interacts with both GSK-3β and E3 lig- ases and facilitates the proteasomal degradation of GSK-3β. The 3D models of GSK-3β and E3 Ligase were predicted using AlphaFold, and the PROTAC structure was obtained from previous research and was designed using the YASARA software. Finally, the GSK-3β protein and PROTAC interactions were computed using the HDOCK software.  The interactions between the GSK-3β–E3 ligase complex and  the PROTAC molecule were identified using the Protein–Ligand Interaction Profiler (PLIP) analysis tool. The binding energy was calculated using the PRODIGY software. These results show that PROTAC P2 could be the most appropriate candidate for this research since it has the highest binding affinity of -9.2 kcal/mol. Finally, I have explored the basis of protein–protein interactions by considering the electro- static surface potential and hydrophobicity as contributing factors. The current study will pave the way for PROTAC-based therapeutics targeting GSK-3β as a treatment for AD.