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Molecular Investigations of Protriptyline as a Multi-Target Directed Ligand in Alzheimer's Disease

Alzheimer's disease (AD) is a complex neurodegenerative disorder involving multiple cellular and molecular processes. The discovery of drug molecules capable of targeting multiple factors involved in AD pathogenesis would greatly facilitate in improving therapeutic strategies. The repositioning...

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Autores principales: Bansode, Sneha B., Jana, Asis K., Batkulwar, Kedar B., Warkad, Shrikant D., Joshi, Rakesh S., Sengupta, Neelanjana, Kulkarni, Mahesh J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4139341/
https://www.ncbi.nlm.nih.gov/pubmed/25141174
http://dx.doi.org/10.1371/journal.pone.0105196
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author Bansode, Sneha B.
Jana, Asis K.
Batkulwar, Kedar B.
Warkad, Shrikant D.
Joshi, Rakesh S.
Sengupta, Neelanjana
Kulkarni, Mahesh J.
author_facet Bansode, Sneha B.
Jana, Asis K.
Batkulwar, Kedar B.
Warkad, Shrikant D.
Joshi, Rakesh S.
Sengupta, Neelanjana
Kulkarni, Mahesh J.
author_sort Bansode, Sneha B.
collection PubMed
description Alzheimer's disease (AD) is a complex neurodegenerative disorder involving multiple cellular and molecular processes. The discovery of drug molecules capable of targeting multiple factors involved in AD pathogenesis would greatly facilitate in improving therapeutic strategies. The repositioning of existing non-toxic drugs could dramatically reduce the time and costs involved in developmental and clinical trial stages. In this study, preliminary screening of 140 FDA approved nervous system drugs by docking suggested the viability of the tricyclic group of antidepressants against three major AD targets, viz. Acetylcholinesterase (AChE), β-secretase (BACE-1), and amyloid β (Aβ) aggregation, with one member, protriptyline, showing highest inhibitory activity. Detailed biophysical assays, together with isothermal calorimetry, fluorescence quenching experiments, kinetic studies and atomic force microscopy established the strong inhibitory activity of protriptyline against all three major targets. The molecular basis of inhibition was supported with comprehensive molecular dynamics simulations. Further, the drug inhibited glycation induced amyloid aggregation, another important causal factor in AD progression. This study has led to the discovery of protriptyline as a potent multi target directed ligand and established its viability as a promising candidate for AD treatment.
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spelling pubmed-41393412014-08-25 Molecular Investigations of Protriptyline as a Multi-Target Directed Ligand in Alzheimer's Disease Bansode, Sneha B. Jana, Asis K. Batkulwar, Kedar B. Warkad, Shrikant D. Joshi, Rakesh S. Sengupta, Neelanjana Kulkarni, Mahesh J. PLoS One Research Article Alzheimer's disease (AD) is a complex neurodegenerative disorder involving multiple cellular and molecular processes. The discovery of drug molecules capable of targeting multiple factors involved in AD pathogenesis would greatly facilitate in improving therapeutic strategies. The repositioning of existing non-toxic drugs could dramatically reduce the time and costs involved in developmental and clinical trial stages. In this study, preliminary screening of 140 FDA approved nervous system drugs by docking suggested the viability of the tricyclic group of antidepressants against three major AD targets, viz. Acetylcholinesterase (AChE), β-secretase (BACE-1), and amyloid β (Aβ) aggregation, with one member, protriptyline, showing highest inhibitory activity. Detailed biophysical assays, together with isothermal calorimetry, fluorescence quenching experiments, kinetic studies and atomic force microscopy established the strong inhibitory activity of protriptyline against all three major targets. The molecular basis of inhibition was supported with comprehensive molecular dynamics simulations. Further, the drug inhibited glycation induced amyloid aggregation, another important causal factor in AD progression. This study has led to the discovery of protriptyline as a potent multi target directed ligand and established its viability as a promising candidate for AD treatment. Public Library of Science 2014-08-20 /pmc/articles/PMC4139341/ /pubmed/25141174 http://dx.doi.org/10.1371/journal.pone.0105196 Text en © 2014 Bansode et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Bansode, Sneha B.
Jana, Asis K.
Batkulwar, Kedar B.
Warkad, Shrikant D.
Joshi, Rakesh S.
Sengupta, Neelanjana
Kulkarni, Mahesh J.
Molecular Investigations of Protriptyline as a Multi-Target Directed Ligand in Alzheimer's Disease
title Molecular Investigations of Protriptyline as a Multi-Target Directed Ligand in Alzheimer's Disease
title_full Molecular Investigations of Protriptyline as a Multi-Target Directed Ligand in Alzheimer's Disease
title_fullStr Molecular Investigations of Protriptyline as a Multi-Target Directed Ligand in Alzheimer's Disease
title_full_unstemmed Molecular Investigations of Protriptyline as a Multi-Target Directed Ligand in Alzheimer's Disease
title_short Molecular Investigations of Protriptyline as a Multi-Target Directed Ligand in Alzheimer's Disease
title_sort molecular investigations of protriptyline as a multi-target directed ligand in alzheimer's disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4139341/
https://www.ncbi.nlm.nih.gov/pubmed/25141174
http://dx.doi.org/10.1371/journal.pone.0105196
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