Identification of Potential Plant-Based Bioactive Compounds as α-Synuclein Targets via Molecular Docking and Molecular Dynamics Simulations

Introduction

Parkinson’s Disease (PD) is a distressing neurodegenerative ailment that involves the demise of neurons present in dopaminergic system and continuous progression of α-synuclein into amyloid fibrils. Combating α-synuclein aggregation represents an intriguing approach to develop disease-modifying therapy.

Materials and Methods

This work encompasses a systematic in silico design to evaluate plant-based benzoquinone and its derivatives Vilangin, phenyl-Vilangin, and methyl-Vilangin, against the α-synuclein fibril structure (PDB ID: 2N0A). Molecular docking was performed at three reported functional binding pockets (Sites 2, 3/13, and 9) to determine the binding affinity and interaction profiles. The most promising complexes were subsequently subjected to 200-ns molecular dynamics simulations using the CHARMM force field. The root mean square deviation, the root mean square fluctuation, principal component analysis, and free energy landscape profiling were used to evaluate structural stability and conformational behaviour.

Results

The docking results identified phenyl-Vilangin as the strongest binder, particularly at Site 3/13 (ΔG=-7.9 kcal/mol), followed by vilangin, while methyl-vilangin showed comparatively weaker interactions. Molecular dynamics simulations confirmed enhanced structural stabilisation in the α-synuclein-phenyl-vilangin complex, characterised by lower conformational deviation, reduced residue-level fluctuations, restricted essential motions, and well-defined low-energy conformational basin.

Conclusion

Overall, phenyl-vilangin emerged as the most promising scaffold for targeting α-synuclein aggregation, warranting further experimental validation.