Inhibitory action of indanone-carbamate hybrid molecules on the aggregation of Aβ16−22 peptides and their translocation across POPC lipid bilayer

The aggregation of Aβ peptides leads to Alzheimer's Disease (AD), the most common kind of dementia. This neurodegenerative disease has no permanent cure to date. Drug design for Alzheimer's is, therefore, a major challenge to the scientific community. A recent experimental study showed the potency of two indanone-carbamate-based molecules to act as drugs against AD. However, the central molecular mechanism of action of these inhibitors is unknown. For knowing the mechanism of amyloid aggregation and the role of these novel molecules as inhibitors, an extensive all-atom molecular dynamics simulation of the Aβ16−22 peptides is performed. A variety of analyses are carried out to explore the structural change of the peptides in an aqueous medium in the absence and presence of inhibitors viz. secondary structure analysis, solvent accessible surface area calculation, residue-wise and Cα atom-wise contact mapping. In order to identify the peptide's residues associated with amyloid aggregation and interaction with the inhibitor, nonbonding interaction energies, radial distribution functions, coordination number, hydrogen bonds, and potential of mean forces are estimated. The central hydrophobic core, more importantly, the aromatic phenylalanine residues are found to play a substantial role in the formation of toxic amyloid oligomers. All the analyses demonstrate diminishing interpeptide interactions in presence of the inhibitors thereby checking amyloid aggregation. The molecules are also found to destabilize preformed amyloid fibrils. Furthermore, permeation properties of these small molecule inhibitors are investigated across a model POPC lipid bilayer, revealing their biocompatibility and translocation mechanisms.