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.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Medicinal Chemistry, Federal University of Alagoas, Nursing and Pharmacy School, Maceio-AL, Brazil.
authors.forename: Edeildo F
authors.initials: EF
authors.lastname: Silva-Junior
authors.affiliation: Chemistry and Biotechnology Institute, Federal University of Alagoas, Maceio-AL, Brazil.
authors.forename: Paulo H
authors.initials: PH
authors.lastname: Barcellos Franca
authors.affiliation: University of Sergipe, Postgraduate Program in Health Science, Aracaju-SE, Brazil.
authors.forename: Lucindo J
authors.initials: LJ
authors.lastname: Quintans-Junior
authors.affiliation: State University of Paraiba, Laboratory of Synthesis and Drug Delivery, Joao Pessoa-PB, Brazil.
authors.forename: Francisco J B
authors.initials: FJB
authors.lastname: Mendonca-Junior
authors.affiliation: Federal University of Paraíba, Joao Pessoa-PB, Brazil.
authors.forename: Luciana
authors.initials: L
authors.lastname: Scotti
authors.affiliation: Federal University of Paraíba, Joao Pessoa-PB, Brazil.
authors.forename: Marcus T
authors.initials: MT
authors.lastname: Scotti
authors.affiliation: Laboratory of Medicinal Chemistry, Federal University of Alagoas, Nursing and Pharmacy School, Maceio-AL, Brazil.
authors.forename: Thiago M
authors.initials: TM
authors.lastname: de Aquino
authors.affiliation: Laboratory of Medicinal Chemistry, Federal University of Alagoas, Nursing and Pharmacy School, Maceio-AL, Brazil.
authors.forename: Joao X
authors.initials: JX
authors.lastname: de Araujo-Junior
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D020134:Catalytic Domain / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding
chemical_list: D002800:Cholinesterase Inhibitors; D008024:Ligands; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: Alzheimer`s disease; DFT; acetylcholinesterase.; dynamic simulations; molecular docking; β-secretase