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

Abstract

Parkinson's disease (PD), a rapidly growing neurodegenerative disorder, is characterized by intracellular α-synuclein aggregates. The tyrosine kinase c-Abl plays a critical role in PD pathogenesis. This study aimed to identify novel c-Abl inhibitors from natural products using molecular docking and dynamics simulations. We explored phytochemicals from Indian Medicinal Plants, Phytochemistry and Therapeutics (IMPPAT) database and employed molecular docking and molecular dynamics to discover c-Abl inhibitors. Three potential hits: IMPHY008934, IMPHY009589, and IMPHY006310 were identified. These compounds demonstrated comparable binding affinity to Nilotinib, a comparison drug. Toxicity predictions revealed IMPHY008934 and IMPHY009589 exhibited lower toxicity than Nilotinib. Molecular dynamics simulations confirmed the stability of IMPHY009589 and IMPHY008934 with c-Abl. Density functional theory (DFT) analysis showed that IMPHY006310 and IMPHY008934 displayed enhanced reactivity and polarizability. Our findings suggest these natural compounds may target c-Abl in PD pathogenesis and possibly downregulate the overexpressed α-synuclein and may serve as promising leads for PD therapy.