A Boron-Containing Compound Acting on Multiple Targets Against Alzheimer's Disease. Insights from Ab Initio and Molecular Dynamics Simulations

Given the multifactorial nature and pathogenesis of Alzheimer's disease, therapeutic strategies are addressed to combine the benefits of every single-target drug into a sole molecule. Quantum mechanics and molecular dynamics (MD) methods were employed here to investigate the multitarget action of a boron-containing compound against Alzheimer's disease. The antioxidant activity as a radical scavenger and metal chelator was explored by means of density functional theory. The most plausible radical scavenger mechanisms, which are hydrogen transfer, radical adduct formation, and single-electron transfer in aqueous and lipid environments, were fully examined. Metal chelation ability was investigated by considering the complexation of Cu(II) ion, one of the metals that in excess can even catalyze the β-amyloid (Aβ) aggregation. The most probable complexes in the physiological environment were identified by considering both the stabilization energy and the shift of the λmax induced by the complexation. The excellent capability to counteract Aβ aggregation was explored by performing MD simulations on protein-ligand adducts, and the activity was compared with that of curcumin, chosen as a reference.