Computational phytochemical screening for Parkinson's disease therapeutics: c-Abl and beyond

Area of Science:

• Neuroscience
• Pharmacology
• Computational Chemistry

Background:

• Parkinson's disease (PD) is a growing neurodegenerative disorder linked to alpha-synuclein aggregates.
• The tyrosine kinase c-Abl is implicated in the pathogenesis of Parkinson's disease.

Purpose of the Study:

• To identify novel c-Abl inhibitors from natural products.
• To evaluate the potential of these natural compounds as therapeutic leads for Parkinson's disease.

Main Methods:

• Utilized molecular docking and dynamics simulations.
• Screened phytochemicals from the IMPPAT database.
• Performed toxicity predictions and Density Functional Theory (DFT) analysis.

Main Results:

• Identified three potential c-Abl inhibitors: IMPHY008934, IMPHY009589, and IMPHY006310.
• Compounds showed comparable binding affinity to Nilotinib; IMPHY008934 and IMPHY009589 had lower predicted toxicity.
• Molecular dynamics confirmed the stability of IMPHY009589 and IMPHY008934 with c-Abl; DFT indicated enhanced reactivity for IMPHY006310 and IMPHY008934.

Conclusions:

• The identified natural compounds may target c-Abl in Parkinson's disease.
• These compounds could potentially downregulate overexpressed alpha-synuclein.
• Natural products represent promising leads for novel Parkinson's disease therapeutics.