QSAR-Guided Virtual Screening and Molecular Dynamics Reveal Olaparib as a Repurposing Lead Against α-Synuclein...

Area of Science:

• Computational chemistry
• Drug discovery
• Neurodegenerative diseases

Background:

• Parkinson's disease (PD) involves alpha-synuclein (α-syn) aggregation into Lewy bodies.
• Current treatments for PD are not disease-modifying.

Purpose of the Study:

• To repurpose FDA-approved drugs as inhibitors of α-syn fibrils.
• To identify novel therapeutic leads for Parkinson's disease.

Main Methods:

• Integrated computational pipeline: QSAR modeling, virtual screening, MD simulations, MM-PBSA calculations.
• QSAR models trained on α-syn binding affinity data.
• Docking against α-syn fibril structure (PDB 6SSX) to identify potential inhibitors.

Main Results:

• Olaparib identified as a high-affinity inhibitor, binding to the NAC groove of α-syn fibrils.
• Olaparib showed stable binding in MD simulations with significant binding free energy (ΔG = -20.6 ± 1.9 kcal/mol).
• Paliperidone and Risperidone also showed binding but are secondary binders, not therapeutic leads due to side effects.

Conclusions:

• Olaparib is a promising repurposing candidate for Parkinson's disease therapy.
• Computational methods can effectively identify potential drug candidates for neurodegenerative diseases.
• Experimental validation of identified compounds is warranted.