Reactivity and Electronic Structure Alterations of Crizotinib in the Presence of Neurotoxic β-Amyloid Aggregates

Crizotinib, a known tyrosine kinase inhibitor in cancer treatment, is investigated here for its interactions with neurodegenerative disease-related biomolecules, specifically beta-amyloid (Aβ42) peptides. Using Density Functional Theory (DFT) with the B3LYP/6-31G(d,p) method, Crizotinib’s molecular structure was optimized to ensure stability. Molecular dynamics (MD) simulations were conducted with GROMACS, applying the CHARMM force field for peptides and GAFF for Crizotinib. The simulation involved solvating the system, neutralizing it, and running a 100-nanosecond production under physiological conditions. Electronic structure analysis through DFT provided insight into the Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO) distributions of Crizotinib both with and without Aβ42. The results revealed notable shifts in Crizotinib’s electronic properties upon interaction with Aβ42, indicating altered chemical reactivity and binding potential. Specifically, an expanded electron cloud suggested that non-covalent interactions, such as hydrogen bonding and π-π stacking, play a role in these changes. These findings propose that Crizotinib could influence Aβ42-related pathways, which are central to Alzheimer’s disease. The study emphasizes the value of computational tools in exploring drug interactions with neurotoxic peptides and suggests potential therapeutic relevance of Crizotinib in neurodegenerative disorders.