In silico screening of peptide inhibitors targeting α-synuclein for Parkinson's disease

Parkinson's disease affects cognitive, motor, and autonomic functions due to nervous system degeneration. Though no cure exists, medications and therapies can help alleviate symptoms, but their effectiveness diminishes as the disease progresses, ultimately increasing the need for alternative treatments. α-Synuclein has long been one of the main targets in addressing Parkinson's through drug design studies, but no drugs are yet approved against α-Synuclein aggregation. Therefore, this study aims to develop potential inhibitors of fibrillization by screening thousands of peptides in terms of their binding abilities via Molecular Docking and Molecular Dynamics simulations. Our results show that peptides with Lysine and Arginine at terminal groups result in higher binding affinities to the C-terminal domain. Among the heptapeptides examined, RWRRKRL shows the highest binding free energy to the protein while KKRHKWR exhibits superior stabilizing effect, interacting with both N- and C-terminal regions of α-Synuclein. The inhibitory potential of peptides on the fibrillar structure of protein varies with concentration, and RWRRKRL at 1:3 protein-peptide monomer ratio shows promise as an inhibitor by reducing the internal H-bonds of the protein and increasing RMSD values. These results reveal that short-chain peptides can be designed against α-Synuclein oligomerization offering a potential therapeutic approach for preventing Parkinson's.