Computational Modeling of PROTAC-Induced Targeted Degradation of Tau Protein in Alzheimer’s Disease
DOI:
https://doi.org/10.58445/rars.2771Keywords:
PROTAC, Alzheimer’s Disease, Tau Protein Degradation, Molecular Docking, Targeted Protein DegradationAbstract
Alzheimer’s disease (AD) is a progressive disease that destroys memory and other mental functions. It is a type of dementia primarily affecting older adults, causing a decline in cognitive abilities, behavior, and social skills severe enough to interfere with daily life. Tau is a protein that plays a key role in AD by forming abnormal clumps called neurofibrillary tangles inside brain cells when it becomes misfolded and accumulates, which disrupts the normal function of neurons and contributes significantly to the cognitive decline associated with the disease. PROTAC is a small molecule that degrades harmful proteins by binding to a target protein, recruiting E3 ubiquitin ligase, labeling the protein with a ubiquitin tag, and then degrading the protein. We hypothesize that a chemical alteration in the PROTAC 3D structure could make a stronger binding PROTAC. PROTAC binds to the tau protein and the E3 ubiquitin ligase,
disintegrating the fibrils. The HDOCK web server allowed protein-protein and protein-DNA/RNA docking based on a hybrid strategy. Two molecular docking simulations were performed to understand the interactions between the fibril-PROTAC and E3 Ligase-PROTAC. Finally, the complete Fibril-PROTAC-E3 Ligase complex was formed. A PLIP interaction analysis was performed to understand interactions between the PROTAC and protein (tau and E3 Ligase). Finally, based on the docking analysis, the PROTAC was chemically modified to enhance its binding affinity. The application of PROTAC research for AD lies in developing targeted therapies to degrade disease-related proteins, potentially improving treatment outcomes.
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