Identification of a Novel Multifunctional Ligand for Simultaneous Inhibition of Amyloid-Beta (Aβ42) and Chelation of Zinc Metal Ion

Zinc binding to beta-amyloid structure could promote amyloid-beta aggregation, as well as reactive oxygen species (ROS) production, as suggested in many experimental and theoretical studies. Therefore, the introduction of multifunctional drugs capable of chelating zinc metal ion and inhibiting A aggregation is a promising strategy in the development of AD treatment. The present study has evaluated the efficacy of a new bifunctional peptide drug using molecular docking and molecular dynamics (MD) simulations. This drug comprises two different domains, an inhibitor domain, obtained from the C-terminal hydrophobic region of A beta, and a Zn2+ chelating domain, derived from rapeseed meal, merge with a linker. The multifunctionality of the ligand was evaluated using a comprehensive set of MD simulations spanning up to 3.2 mu s including A beta relaxation, ligand-Zn2+ bilateral interaction, and, more importantly, ligand-Zn2+-A beta(42) trilateral interactions. Analysis of the results strongly indicated that the bifunctional ligand can chelate zinc metal ion and avoid A beta aggregation simultaneously. The present study illustrated that the proposed ligand has considerable hydrophobic interactions and hydrogen bonding with monomeric A beta in the presence of zinc metal ion. Therefore, in light of these considerable interactions and contacts, the alpha-helical structure of A beta has been enhanced, while the beta-sheet formation is prevented and the alpha-helix native structure is protected. Furthermore, the analysis of interactions between A beta and ligand-zinc complex revealed that the zinc metal ion is coordinated to Met13, the ending residue of the ligand and merely one residue in A beta. The results have proven the previous experimental and theoretical findings in the literature about A beta interactions with zinc metal ion and also A beta interactions with the first domain of the proposed ligand. Moreover, the current research has evaluated the chelation using MD simulation and linear interaction energy (LIE) methods, and the result has been satisfactorily verified with previous experimental and theoretical (DFT) studies.