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Proteins. 2013 Jul;81(7):1179-91. doi: 10.1002/prot.24267. Epub 2013 Apr 10.

Interaction of metal chelators with different molecular forms of acetylcholinesterase and its significance in Alzheimer's disease treatment.

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DRDO-BU Center for Life Sciences, Bharathiar University, Coimbatore 641046, Tamil Nadu, India.


The peripheral anionic site (PAS) of acetylcholinesterase (AChE) is involved in amyloid beta (Aβ) peptides aggregation of Alzheimer's disease (AD). AChE exhibits an aryl acylamidase (AAA) activity along with the well known esterase activity. Numerous studies have reported the beneficiary effect of metal chelators in AD treatment. Hence, a comparative study on the effect of metal chelators on both the esterase and AAA activity of AChE globular (G4 and G1) molecular forms was performed. The inhibitory effect of 1,10-phenanthroline was high towards AChE esterase activity. The corresponding IC50 values for esterase activity of G4 and G1-form was 190 µM and 770 µM and for AAA activity it was 270 µM and 2.74 mM, respectively. Kinetic studies on both forms of AChE show that 1,10-phenanthroline inhibits esterase in competitive and AAA activity in non-competitive manner. Protection studies further revealed that the nature of 1,10-phenanthroline inhibition on AChE is through its direct binding to protein rather than its metal chelation property. Molecular docking studies shows orientation of 1,10-phenathroline in the PAS through hydrophobic interactions with the PAS residues (Trp286, Tyr124 and Tyr341) and hydrogen bonding with Phe295. Further molecular dynamics simulation of "hAChE-1,10-phenanthroline" complex revealed that both hydrogen and hydrophobic interaction contribute equally for 1,10-phenanthroline binding to hAChE. Such an interaction of 1,10-phenanthroline on PAS may hinder "AChE-Aβ peptide" complex formation. Hence, 1,10-phenanthroline can act as a lead molecule for developing drug(s) against AD ailment with dual functions namely, anti-cholinesterase and anti-amyloid aggregation potency in a single chemical entity.

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