EVALUATION OF NOVEL LIGAND FOR THE MAINTENANCE OF NATIVE Aβ(1-42) PEPTIDE CONFORMATION: RELEVANCE TO ALZHEIMER’S DISEASE

Alzheimer’s disease (AD) is a disorder of the central nervous system with progressive neurodegeneration, cognition, and memory loss. A major molecular hallmark of the disorder includes extracellular deposition of the Amyloid beta-peptide (Aβ) in senile plaques, the appearance of intracellular neurofibrillary tangles. The Aβ peptide is produced by sequential cleavage of the Amyloid precursor protein (APP) by α, β, and γ-secretase. The secretase β and γ generate a number of isoforms of peptides containing 36-43 amino acid residues in length. The mainly universal isoforms are Aβ_(1-40) and Aβ_(1-42). Aβ_(1-42) C-terminal domain (29-42 amino acid residues) adopts β conformation, and the N-terminal domain (10-24 amino acid residues) facilitates a dynamic equilibrium between α- helix and β-strand. Thus Aβ polymerization requires unfolding of the native α-helical structure of Aβ. Stabilization of the Aβ central α- helix is an efficient step to foil the Aβ polymerization. Here we report test compounds which to bind and stabilize the 11-30 amino acid regions of Aβ_(1-42) in α-helical conformation. On docking, the ligands with Aβ peptide followed by Molecular dynamics simulation for 20ns favored the identification of test compound NIAID. That postulated to bind and stabilize the Aβ central α-helix. So stabilization of Aβ secondary structure with a ligand that maintains the α-helical conformation may provide clues in developing drugs to control the Aβ deposition observed in AD patients.