Background: The most important hallmark in the neuropathology of Alzheimer's disease (AD) is the formation of amyloid-β (Aβ) fibrils due to the misfolding/aggregation of the Aβ 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 Aβ42 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 Aβ peptide and a set of curcumin derivatives previously explored in experimental assays.
Methods: The interactions of ten ligands with Aβ 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 Aβ42 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 Aβ42 monomers when compared to a double substitution. In addition, the molecular docking simulations showed that the interaction between the curcumin derivatives and the Aβ42 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 Aβ 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.
Keywords: Alzheimer’s disease; AutoDock 4; AutoDock Vina; Aβ monomer; Aβ42 fibril; Smina; curcumin; curcumin derivatives; molecular docking.