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

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 A beta(42) aggregation, metal-induced A beta(42) aggregation, reactive oxygen species (ROS) generation, and rescues SH-SY5Y cells from A beta(42) 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 A beta(42) and a pentameric protofibril structure of A beta(42). Compound 6n binds preferably to the central hydrophobic core (CHC) and C-terminal regions of the A beta(42) monomer as well as the protofibril structure. The secondary structure analysis suggests that 6n prevents the aggregation of the A beta(42) monomer and disaggregates A beta(42) protofibrils by sustaining the helical content in the A beta(42) monomer and converting the beta-sheet into random coil conformation in the A beta(42) protofibril structure. A significant decrease in the average number of hydrogen bonds, binding affinity, and residue-residue contacts between chains D-E of the A beta(42) protofibril in the presence of 6n indicates destabilization of the A beta(42) protofibril structure. The MM-PBSA (molecular mechanics Poisson-Boltzmann surface area) analysis highlighted favourable binding free energy (Delta G(binding)) for the A beta(42) monomer-6n and A beta(42) protofibril-6n complex. Overall, MD results highlighted that 6n stabilizes the native alpha-helix conformation of the A beta(42) monomer and induces a sizable destabilization in the A beta(42) 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.