Computational Modeling of PROTAC-Induced Targeted Degradation of Alpha-Synuclein in Parkinson’s Disease

Parkinson’s disease is a neurodegenerative disease that takes a heavy toll on the patient’s motor skills as the protein alpha-synuclein aggregates the susbstania niagra in the brain, causing symptoms like tremors, speech and writing difficulties, and muscle stiffness. The alpha-synuclein protein attacks brain cells and obstructs the brain’s ability to perform everyday functions effectively. Despite the magnitude of this neurological disorder, PROTACs (Proteolysis Targeting Chimera), designed to degrade targeted proteins, can act as a potential solution for controlling the abundance of alpha-synuclein. We hypothesize that the alpha-synuclein protein binds to the E3 Ligase protein with the help of PROTAC. Our second hypothesis is that chemical alteration in the PROTAC structure could potentially develop more potent PROTACs. We have used the HADDOCK software to dock the α-Synuclein and the E3 Ligase to form an α-Synuclein_E3 Ligase complex. In the next step, we chemically alter the PROTAC to obtain 10 PROTACs. Combine the α-Synuclein-E3 Ligase complex with the 10 PROTACS to create a final complex—α-Synuclein-E3 Ligase- PROTAC complex analysis using PLIP software. We successfully modeled α-Synuclein and E3 Ligase binding and got α-Synuclein-E3 Ligase complex. We found that PROTAC P1 and P2 were the most ap- propriate PROTAC for binding to both proteins by interacting with them. The work helps in under- standing the α-Synuclein and E3 Ligase interaction mechanism. Found appropriate PROTAC binding to α-Synuclein-E3 Ligase complex.