All-atom molecular dynamics simulations were performed on the A�42 monomer at its a-helical conformation and a pentamer fibril fragment of A�42 peptide with or without the drug candidates of LRL and Fluorene series compounds to investigate the mechanism of inhibition. The results showed that the active drug candidates LRL22 (EC50 = 0.734 �M) and K162 (EC50 = 0.080 �M), stabilize the hydrophobic core I of Ab42 peptide (residues 17-23) to its a-helical conformation by interacting specifically in this region. The non-active drug candidates (LRL27, EC50 > 10 �M; K182, EC50 > 5 �M) have little similar effect or none at all. This explains the different behavior of the drug candidates in experiments. it indicates that the hydrophobic core I of Ab42 peptide plays a major mechanistic role in formation of the amyloid fibrils.

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

244th National Meeting (2012)

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