Title:Dynamic Simulation, Docking and DFT Studies Applied to a Set of Anti-Acetylcholinesterase Inhibitors in the enzyme β-Secretase (BACE-1): An Important Therapeutic Target in Alzheimer's Disease
VOLUME: 13 ISSUE: 4
Author(s):Edeildo F. Silva-Junior, Paulo H. Barcellos Franca, Lucindo J. Quintans-Junior, Francisco J. B. Mendonca-Junior, Luciana Scotti, Marcus T. Scotti, Thiago M. de Aquino and Joao X. de Araujo-Junior*
Affiliation:Laboratory of Medicinal Chemistry, Federal University of Alagoas, Nursing and Pharmacy School, Maceio-AL, Chemistry and Biotechnology Institute, Federal University of Alagoas, Maceio-AL, University of Sergipe, Postgraduate Program in Health Science, Aracaju-SE, State University of Paraiba, Laboratory of Synthesis and Drug Delivery, Joao Pessoa-PB, Federal University of Paraíba, Joao Pessoa-PB, Federal University of Paraíba, Joao Pessoa-PB, Laboratory of Medicinal Chemistry, Federal University of Alagoas, Nursing and Pharmacy School, Maceio-AL, Nursing and Pharmacy School, Federal University of Alagoas, P.O. Box: 57072-900, Maceio
Keywords:β-secretase, molecular docking, dynamic simulations, DFT, Alzheimer's disease, acetylcholinesterase.
Abstract:Background: Alzheimer's disease (AD) affects mainly elderly people over 60 years of age.
Currently, there are more than 35 million people with this disease worldwide. The enzyme β-secretase
is involved in the processing of the amyloid precursor protein and plays a key role in the physiopathology
of AD. The action of some acetylcholinesterase inhibitors (AChEI) as β-secretase inhibitors has
been reported.
Objective: The aim of this study was to highlight the modes of the binding of acetylcholinesterase
ligands onto the active site of the β-secretase enzyme.
Methods: Molecular dynamics and docking were used in order to identify pivotal interactions that favor
the inhibitory activity and provide a rational basis for planning novel β-secretase inhibitors. Additionally,
density functional theory (DFT) was used to provide accurate energy values for the complexes.
A mechanistic study of the amide hydrolysis was also performed at the M06/6-31G(d) basis set.
Results: Of the 100 AChE inhibitors, 10 were able to interact with Asp32 and/or Asp228 residues from
the enzyme BACE-1, suggesting that these could act as multi-target compounds. These inhibitors were
selected for DFT studies in order to provide more accurate energy values. Interestingly, the range of
energy values (-27.01 to -8.64 kJ mol-1) obtained was in agreement with the anti-AChE activity. The
results obtained in the mechanistic study of compound 93 using DFT are in agreement with theoretical
studies described in the literature.
Conclusion: The results reported in this study will advance our understanding of the influence of the
distinct chemical structures of inhibitors at the active site and aid the development of new virtual
screening protocols to design novel AChE multi-target inhibitors.
