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Indirect-acting cholinergic agonists are agents that interact with the acetylcholinesterase enzyme in the synaptic cleft, preventing the breakdown of acetylcholine into choline and acetate. Consequently, the concentration of acetylcholine in the synaptic cleft increases. These agonists can be classified into reversible and irreversible inhibitors based on their duration of action.
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Development of Potential Multi-Target Inhibitors for Human Cholinesterases and Beta-Secretase 1: A Computational

Deyse B Barbosa1, Mayra R do Bomfim1, Tiago A de Oliveira2

  • 1Laboratório de Modelagem Molecular, Departamento de Saúde, Universidade Estadual de Feira de Santana, Feira de Santana 44036-900, BA, Brazil.

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|December 23, 2023
PubMed
Summary

This study identified ZINC1733 as a potential inhibitor for acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and BACE-1, key enzymes in Alzheimer's disease. Further testing is planned to confirm its therapeutic potential for neurodegenerative disease.

Keywords:
Alzheimer’s diseasemolecular dockingmolecular dynamicspharmacophore modeltriple inhibitors

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Computational Chemistry

Background:

  • Alzheimer's disease (AD) is the primary cause of dementia, characterized by chronic neurodegeneration.
  • AD pathogenesis involves the cholinergic and amyloid pathways, making their key enzymes targets for therapy.
  • Simultaneous inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and beta-secretase 1 (BACE-1) offers a promising therapeutic strategy.

Purpose of the Study:

  • To identify novel multi-target inhibitors for AChE, BuChE, and BACE-1.
  • To utilize molecular modeling and virtual screening to discover potential therapeutic agents for Alzheimer's disease.
  • To find compounds that simultaneously inhibit key enzymes in both cholinergic and amyloid pathways.

Main Methods:

  • Pharmacophore modeling based on the active sites of AChE, BuChE, and BACE-1.
  • Virtual screening of molecular libraries using the developed pharmacophore model.
  • Molecular docking simulations to assess binding affinity to the target enzymes.
  • Evaluation of physicochemical properties, toxicological parameters, and commercial availability of top candidates.
  • Molecular dynamics simulations to analyze the stability of the most promising inhibitor-enzyme complex.

Main Results:

  • A pharmacophore model was constructed, featuring hydrophobic centers, hydrogen bond acceptors, and a positively charged nitrogen.
  • Twelve compounds demonstrated adequate docking scores against all three target enzymes.
  • ZINC1733 exhibited the highest inhibitory potential against AChE, BuChE, and BACE-1.
  • Molecular dynamics simulations confirmed the stability of the ZINC1733-enzyme systems.

Conclusions:

  • The in silico approach successfully identified ZINC1733 as a potential multi-target inhibitor for AChE, BuChE, and BACE-1.
  • ZINC1733 represents a promising candidate for further investigation as an Alzheimer's disease therapeutic agent.
  • Future enzymatic assays are necessary to experimentally validate the predicted inhibitory activity of ZINC1733.