Computational Evaluation Of Interaction Between Curcumin Derivatives And Amyloid-Beta Monomers And Fibrils: Relevance To Alzheimer'S Disease

Background: The most important hallmark in the neuropathology of Alzheimer's disease (AD) is the formation of amyloid-beta (A beta) fibrils due to the misfolding/aggregation of the A beta peptide. Preventing or reverting the aggregation process has been an active area of research. Naturally occurring products are a potential source of molecules that may be able to inhibit A beta(42) peptide aggregation. Recently, we and others reported the anti-aggregating properties of curcumin and some of its derivatives in vitro, presenting an important therapeutic avenue by enhancing these properties.Objective: To computationally assess the interaction between A beta peptide and a set of curcumin derivatives previously explored in experimental assays.Methods: The interactions of ten ligands with A beta monomers were studied by combining molecular dynamics and molecular docking simulations. We present the in silico evaluation of the interaction between these derivatives and the A beta(42) peptide, both in the monomeric and fibril forms.Results: The results show that a single substitution in curcumin could significantly enhance the interaction between the derivatives and the A beta(42) monomers when compared to a double substitution. In addition, the molecular docking simulations showed that the interaction between the curcumin derivatives and the A beta(42) monomers occur in a region critical for peptide aggregation.Conclusion: Results showed that a single substitution in curcumin improved the interaction of the ligands with the A beta monomer more so than a double substitution. Our molecular docking studies thus provide important insights for further developing/validating novel curcumin-derived molecules with high therapeutic potential for AD.