Alzheimer's disease drug candidates stabilize A-β protein native structure by interacting with the hydrophobic core.

Deposition of amyloid fibrils, consisting primarily of Aβ(40) and Aβ(42) peptides, in the extracellular space in the brain is a major characteristic of Alzheimer's disease (AD). We recently developed new (to our knowledge) drug candidates for AD that inhibit the fibril formation of Aβ peptides and eliminate their neurotoxicity. We performed all-atom molecular-dynamics simulations on the Aβ(42) monomer at its α-helical conformation and a pentamer fibril fragment of Aβ(42) peptide with or without LRL and fluorene series compounds to investigate the mechanism of inhibition. The results show that the active drug candidates, LRL22 (EC(50) = 0.734 μM) and K162 (EC(50) = 0.080 μM), stabilize hydrophobic core I of Aβ(42) peptide (residues 17-21) to its α-helical conformation by interacting specifically in this region. The nonactive drug candidates, LRL27 (EC(50) > 10 μM) and K182 (EC(50) > 5 μM), have little to no similar effect. This explains the different behavior of the drug candidates in experiments. Of more importance, this phenomenon indicates that hydrophobic core I of the Aβ(42) peptide plays a major mechanistic role in the formation of amyloid fibrils, and paves the way for the development of new drugs against AD.