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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4139341?pdf=render |
| _version_ | 1818133721803390976 |
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| author | Sneha B Bansode Asis K Jana Kedar B Batkulwar Shrikant D Warkad Rakesh S Joshi Neelanjana Sengupta Mahesh J Kulkarni |
| author_facet | Sneha B Bansode Asis K Jana Kedar B Batkulwar Shrikant D Warkad Rakesh S Joshi Neelanjana Sengupta Mahesh J Kulkarni |
| author_sort | Sneha B Bansode |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-11T08:57:14Z |
| format | Article |
| id | doaj.art-43e4b6efa6564a54a978d1da8f11c73a |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T08:57:14Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-43e4b6efa6564a54a978d1da8f11c73a2022-12-22T01:13:52ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0198e10519610.1371/journal.pone.0105196Molecular investigations of protriptyline as a multi-target directed ligand in Alzheimer's disease.Sneha B BansodeAsis K JanaKedar B BatkulwarShrikant D WarkadRakesh S JoshiNeelanjana SenguptaMahesh J KulkarniAlzheimer'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.http://europepmc.org/articles/PMC4139341?pdf=render |
| spellingShingle | Sneha B Bansode Asis K Jana Kedar B Batkulwar Shrikant D Warkad Rakesh S Joshi Neelanjana Sengupta Mahesh J Kulkarni Molecular investigations of protriptyline as a multi-target directed ligand in Alzheimer's disease. PLoS ONE |
| 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 |
| url | http://europepmc.org/articles/PMC4139341?pdf=render |
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