Comparative Computational Docking Analysis of MPP+ and Dopamine Binding to Dopamine Transporter in Human and Zebrafish: Mechanistic Insights into MPTP Neurotoxicity

Abstract

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces parkinsonism via its toxic metabolite, 1-methyl-4-phenylpyridinium (MPP+), which structurally mimics dopamine and enters dopaminergic neurons via the dopamine transporter (DAT). To visually depict this mimicry, we performed ligand-protein docking analysis on two species: humans and zebrafish. Human DAT (PDB ID: Q01959) and zebrafish DAT (UniProt ID: Q90ZV1) proteins were prepared with AutoDock Tools. Meanwhile, MPP+ (PubChem ID: CID_39484) and dopamine (PubChem ID: CID_681) ligands were prepared and optimized using the General AMBER Force Field (GAFF) tool. Docking with AutoDock Vina used identical grid parameters of 40 x 40 x 40 [A], which allows blind docking. Binding affinities and interactions were analyzed and visualized using PyMol and LigPlot+. MPP+ exhibited comparable binding affinities to dopamine in both species (human: -7.2 vs -6.1 kcal/mol; zebrafish: -7.6 vs -6.4 kcal/mol), sharing seven out of nine binding residues in humans and nine out of twelve in zebrafish. Spatial overlap with dopamine binding site suggests MPP+ exploits DAT for neuronal entry. However, static docking limitations warrant dynamic validation. This study provides computational evidence for the dopamine-mimetic mechanism of MPP+ but underscores the need for molecular dynamics (MD) simulation and experimental confirmation.