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Pharmacophore-Based Virtual Screening of Novel Competitive Inhibitors of the Neurodegenerative Disease Target Kynurenine-3-Monooxygenase

The pathogenesis of several neurodegenerative diseases such as Alzheimer’s or Huntington’s disease has been associated with metabolic dysfunctions caused by imbalances in the brain and cerebral spinal fluid levels of neuroactive metabolites. Kynurenine monooxygenase (KMO) is considered an ideal ther...

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Autores principales: Gotina, Lizaveta, Seo, Seon Hee, Kim, Chae Won, Lim, Sang Min, Pae, Ae Nim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199213/
https://www.ncbi.nlm.nih.gov/pubmed/34073016
http://dx.doi.org/10.3390/molecules26113314
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author Gotina, Lizaveta
Seo, Seon Hee
Kim, Chae Won
Lim, Sang Min
Pae, Ae Nim
author_facet Gotina, Lizaveta
Seo, Seon Hee
Kim, Chae Won
Lim, Sang Min
Pae, Ae Nim
author_sort Gotina, Lizaveta
collection PubMed
description The pathogenesis of several neurodegenerative diseases such as Alzheimer’s or Huntington’s disease has been associated with metabolic dysfunctions caused by imbalances in the brain and cerebral spinal fluid levels of neuroactive metabolites. Kynurenine monooxygenase (KMO) is considered an ideal therapeutic target for the regulation of neuroactive tryptophan metabolites. Despite significant efforts, the known KMO inhibitors lack blood–brain barrier (BBB) permeability and upon the mimicking of the substrate binding mode, are subject to produce reactive oxygen species as a side reaction. The computational drug design is further complicated by the absence of complete crystal structure information for human KMO (hKMO). In the current work, we performed virtual screening of readily available compounds using several protein–ligand complex pharmacophores. Each of the pharmacophores accounts for one of three distinct reported KMO protein-inhibitor binding conformations. As a result, six novel KMO inhibitors were discovered based on an in vitro fluorescence assay. Compounds VS1 and VS6 were predicted to be BBB permeable and avoid the hydrogen peroxide production dilemma, making them valuable, novel hit compounds for further drug property optimization and advancement in the drug design pipeline.
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spelling pubmed-81992132021-06-14 Pharmacophore-Based Virtual Screening of Novel Competitive Inhibitors of the Neurodegenerative Disease Target Kynurenine-3-Monooxygenase Gotina, Lizaveta Seo, Seon Hee Kim, Chae Won Lim, Sang Min Pae, Ae Nim Molecules Article The pathogenesis of several neurodegenerative diseases such as Alzheimer’s or Huntington’s disease has been associated with metabolic dysfunctions caused by imbalances in the brain and cerebral spinal fluid levels of neuroactive metabolites. Kynurenine monooxygenase (KMO) is considered an ideal therapeutic target for the regulation of neuroactive tryptophan metabolites. Despite significant efforts, the known KMO inhibitors lack blood–brain barrier (BBB) permeability and upon the mimicking of the substrate binding mode, are subject to produce reactive oxygen species as a side reaction. The computational drug design is further complicated by the absence of complete crystal structure information for human KMO (hKMO). In the current work, we performed virtual screening of readily available compounds using several protein–ligand complex pharmacophores. Each of the pharmacophores accounts for one of three distinct reported KMO protein-inhibitor binding conformations. As a result, six novel KMO inhibitors were discovered based on an in vitro fluorescence assay. Compounds VS1 and VS6 were predicted to be BBB permeable and avoid the hydrogen peroxide production dilemma, making them valuable, novel hit compounds for further drug property optimization and advancement in the drug design pipeline. MDPI 2021-05-31 /pmc/articles/PMC8199213/ /pubmed/34073016 http://dx.doi.org/10.3390/molecules26113314 Text en © 2021 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
Gotina, Lizaveta
Seo, Seon Hee
Kim, Chae Won
Lim, Sang Min
Pae, Ae Nim
Pharmacophore-Based Virtual Screening of Novel Competitive Inhibitors of the Neurodegenerative Disease Target Kynurenine-3-Monooxygenase
title Pharmacophore-Based Virtual Screening of Novel Competitive Inhibitors of the Neurodegenerative Disease Target Kynurenine-3-Monooxygenase
title_full Pharmacophore-Based Virtual Screening of Novel Competitive Inhibitors of the Neurodegenerative Disease Target Kynurenine-3-Monooxygenase
title_fullStr Pharmacophore-Based Virtual Screening of Novel Competitive Inhibitors of the Neurodegenerative Disease Target Kynurenine-3-Monooxygenase
title_full_unstemmed Pharmacophore-Based Virtual Screening of Novel Competitive Inhibitors of the Neurodegenerative Disease Target Kynurenine-3-Monooxygenase
title_short Pharmacophore-Based Virtual Screening of Novel Competitive Inhibitors of the Neurodegenerative Disease Target Kynurenine-3-Monooxygenase
title_sort pharmacophore-based virtual screening of novel competitive inhibitors of the neurodegenerative disease target kynurenine-3-monooxygenase
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199213/
https://www.ncbi.nlm.nih.gov/pubmed/34073016
http://dx.doi.org/10.3390/molecules26113314
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