Targeting Dual-Impact FBXO7 Mutants Implicated in Parkinson’s Disease and Cancer: An Integrated Approach Using Density Functional Theory, Molecular Docking, and Molecular Dynamics

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Abstract Cancer and Parkinson's disease (PD), despite their distinct pathologies, exhibit shared molecular mechanisms, particularly involving the dysregulation of autophagy and the ubiquitin-proteasome system. FBXO7 emerges as a crucial protein at the intersection of these diseases, possessing a subset of five mutations with roles in both neurodegeneration and oncogenesis. This study investigates the FP domain of FBXO7 as a therapeutic target; strikingly, three of these mutations are located within the FP domain, underlining its importance as a therapeutic target. We screened a library of 842 covalent inhibitors against the native (PDB ID: 4L9C) and three dual-impact FBXO7 variants (P225L, T249A, R306H). The selected inhibitors were evaluated through ADMET profiling, pharmacophore modeling, and density functional theory (DFT) analyses. Molecular docking was employed to predict binding affinities, and molecular dynamics simulations were conducted to assess protein-ligand complex stability and dynamics. Our findings identify a potential dual inhibitor, C24H25F3N4O2, that addresses a significant research gap, sheds light on this understudied domain, and highlights its potential to modulate both PD and cancer.

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