Artificial Intelligence-Accelerated Drug Discovery and Validation Targeting Synuclein Protein Interactions

Synucleinopathies, including Parkinson's disease (PD), multiple system atrophy, and dementia with Lewy bodies, affect millions globally with higher prevalence in MENA region. While α-synuclein (αS) is crucial for synaptic vesicle trafficking and neurotransmitter release, its pathological aggregation leads to progressive dopaminergic neuronal dysfunction in the substantia nigra. The aggregation of αS into insoluble fibrils and Lewy bodies involves multiple molecular mechanisms, with aberrant protein-protein interactions (aPPIs) playing a key role in driving its pathological effects in diseases like PD. Despite extensive research, directly targeting αS aggregation remains challenging due to its intrinsically disordered structure, dynamic and transient conformations, large hydrophobic surfaces, and its predominantly intracellular localization, which limits drug accessibility.

Hamad Bin Khalifa University (HBKU)