Alzheimer's Disease Drug Candidates Stabilize A-beta Protein Native Structure by Interacting with the Hydrophobic Core

作者：Li Jie; Liu Ruiwu; Lam Kit S; Jin Lee Way; Duan Yong^*

来源：Biophysical Journal, 2011, 100(4): 1076-1082.

DOI：10.1016/j.bpj.2010.12.3741

Deposition of amyloid fibrils, consisting primarily of A beta(40) and A beta(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 A beta peptides and eliminate their neurotoxicity. We performed all-atom molecular-dynamics simulations on the A beta(42) monomer at its alpha-helical conformation and a pentamer fibril fragment of A beta(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 mu M) and K162 (EC(50) = 0.080 mu M), stabilize hydrophobic core I of A beta(42) peptide (residues 17-21) to its a-helical conformation by interacting specifically in this region. The nonactive drug candidates, LRL27 (EC(50) > 10 mu M) and K182 (EC(50) > 5 mu M), 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 A beta(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.

• 出版日期2011-2-16