Interactions of a multifunctional di-triazole derivative with Alzheimer's Aβ42 monomer and Aβ42 protofibril: a systematic molecular dynamics study

Abstract

Amyloid aggregation modulators offer a promising treatment strategy for Alzheimer's disease (AD). We have recently reported a novel di-triazole based compound 6n as a multi-target-directed ligand (MTDL) against AD. 6n effectively inhibits Aβ₄₂ aggregation, metal-induced Aβ₄₂ aggregation, reactive oxygen species (ROS) generation, and rescues SH-SY5Y cells from Aβ₄₂ induced neurotoxicity. However, the underlying inhibitory mechanism remains uncovered. In this regard, molecular dynamics (MD) simulations were performed to understand the effect of 6n on the structure and stability of monomeric Aβ₄₂ and a pentameric protofibril structure of Aβ₄₂. Compound 6n binds preferably to the central hydrophobic core (CHC) and C-terminal regions of the Aβ₄₂ monomer as well as the protofibril structure. The secondary structure analysis suggests that 6n prevents the aggregation of the Aβ₄₂ monomer and disaggregates Aβ₄₂ protofibrils by sustaining the helical content in the Aβ₄₂ monomer and converting the β-sheet into random coil conformation in the Aβ₄₂ protofibril structure. A significant decrease in the average number of hydrogen bonds, binding affinity, and residue–residue contacts between chains D–E of the Aβ₄₂ protofibril in the presence of 6n indicates destabilization of the Aβ₄₂ protofibril structure. The MM-PBSA (molecular mechanics Poisson–Boltzmann surface area) analysis highlighted favourable binding free energy (ΔG_binding) for the Aβ₄₂ monomer–6n and Aβ₄₂ protofibril–6n complex. Overall, MD results highlighted that 6n stabilizes the native α-helix conformation of the Aβ₄₂ monomer and induces a sizable destabilization in the Aβ₄₂ protofibril structure. This work provides theoretical insights into the inhibitory mechanism of 6n against amyloid aggregation and will be beneficial as a molecular guide for structure-based drug design against AD.