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In Silico Identification of Multi-Target Ligands as Promising Hit Compounds for Neurodegenerative Diseases Drug Development

The conventional treatment of neurodegenerative diseases (NDDs) is based on the “one molecule—one target” paradigm. To combat the multifactorial nature of NDDs, the focus is now shifted toward the development of small-molecule-based compounds that can modulate more than one protein target, known as...

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Autores principales: Alov, Petko, Stoimenov, Hristo, Lessigiarska, Iglika, Pencheva, Tania, Tzvetkov, Nikolay T., Pajeva, Ilza, Tsakovska, Ivanka
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9655539/
https://www.ncbi.nlm.nih.gov/pubmed/36362434
http://dx.doi.org/10.3390/ijms232113650
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author Alov, Petko
Stoimenov, Hristo
Lessigiarska, Iglika
Pencheva, Tania
Tzvetkov, Nikolay T.
Pajeva, Ilza
Tsakovska, Ivanka
author_facet Alov, Petko
Stoimenov, Hristo
Lessigiarska, Iglika
Pencheva, Tania
Tzvetkov, Nikolay T.
Pajeva, Ilza
Tsakovska, Ivanka
author_sort Alov, Petko
collection PubMed
description The conventional treatment of neurodegenerative diseases (NDDs) is based on the “one molecule—one target” paradigm. To combat the multifactorial nature of NDDs, the focus is now shifted toward the development of small-molecule-based compounds that can modulate more than one protein target, known as “multi-target-directed ligands” (MTDLs), while having low affinity for proteins that are irrelevant for the therapy. The in silico approaches have demonstrated a potential to be a suitable tool for the identification of MTDLs as promising drug candidates with reduction in cost and time for research and development. In this study more than 650,000 compounds were screened by a series of in silico approaches to identify drug-like compounds with predicted activity simultaneously towards three important proteins in the NDDs symptomatic treatment: acetylcholinesterase (AChE), histone deacetylase 2 (HDAC2), and monoamine oxidase B (MAO-B). The compounds with affinities below 5.0 µM for all studied targets were additionally filtered to remove known non-specifically binding or unstable compounds. The selected four hits underwent subsequent refinement through in silico blood-brain barrier penetration estimation, safety evaluation, and molecular dynamics simulations resulting in two hit compounds that constitute a rational basis for further development of multi-target active compounds against NDDs.
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spelling pubmed-96555392022-11-15 In Silico Identification of Multi-Target Ligands as Promising Hit Compounds for Neurodegenerative Diseases Drug Development Alov, Petko Stoimenov, Hristo Lessigiarska, Iglika Pencheva, Tania Tzvetkov, Nikolay T. Pajeva, Ilza Tsakovska, Ivanka Int J Mol Sci Article The conventional treatment of neurodegenerative diseases (NDDs) is based on the “one molecule—one target” paradigm. To combat the multifactorial nature of NDDs, the focus is now shifted toward the development of small-molecule-based compounds that can modulate more than one protein target, known as “multi-target-directed ligands” (MTDLs), while having low affinity for proteins that are irrelevant for the therapy. The in silico approaches have demonstrated a potential to be a suitable tool for the identification of MTDLs as promising drug candidates with reduction in cost and time for research and development. In this study more than 650,000 compounds were screened by a series of in silico approaches to identify drug-like compounds with predicted activity simultaneously towards three important proteins in the NDDs symptomatic treatment: acetylcholinesterase (AChE), histone deacetylase 2 (HDAC2), and monoamine oxidase B (MAO-B). The compounds with affinities below 5.0 µM for all studied targets were additionally filtered to remove known non-specifically binding or unstable compounds. The selected four hits underwent subsequent refinement through in silico blood-brain barrier penetration estimation, safety evaluation, and molecular dynamics simulations resulting in two hit compounds that constitute a rational basis for further development of multi-target active compounds against NDDs. MDPI 2022-11-07 /pmc/articles/PMC9655539/ /pubmed/36362434 http://dx.doi.org/10.3390/ijms232113650 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Alov, Petko
Stoimenov, Hristo
Lessigiarska, Iglika
Pencheva, Tania
Tzvetkov, Nikolay T.
Pajeva, Ilza
Tsakovska, Ivanka
In Silico Identification of Multi-Target Ligands as Promising Hit Compounds for Neurodegenerative Diseases Drug Development
title In Silico Identification of Multi-Target Ligands as Promising Hit Compounds for Neurodegenerative Diseases Drug Development
title_full In Silico Identification of Multi-Target Ligands as Promising Hit Compounds for Neurodegenerative Diseases Drug Development
title_fullStr In Silico Identification of Multi-Target Ligands as Promising Hit Compounds for Neurodegenerative Diseases Drug Development
title_full_unstemmed In Silico Identification of Multi-Target Ligands as Promising Hit Compounds for Neurodegenerative Diseases Drug Development
title_short In Silico Identification of Multi-Target Ligands as Promising Hit Compounds for Neurodegenerative Diseases Drug Development
title_sort in silico identification of multi-target ligands as promising hit compounds for neurodegenerative diseases drug development
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9655539/
https://www.ncbi.nlm.nih.gov/pubmed/36362434
http://dx.doi.org/10.3390/ijms232113650
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