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Activity Screening of Fatty Acid Mimetic Drugs Identified Nuclear Receptor Agonists

Fatty acid mimetics (FAM) are bioactive molecules acting through the binding sites of endogenous fatty acid metabolites on enzymes, transporters, and receptors. Due to the special characteristics of these binding sites, FAMs share common chemical features. Pharmacological modulation of fatty acid si...

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Autores principales: Helmstädter, Moritz, Schierle, Simone, Isigkeit, Laura, Proschak, Ewgenij, Marschner, Julian Aurelio, Merk, Daniel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9456086/
https://www.ncbi.nlm.nih.gov/pubmed/36077469
http://dx.doi.org/10.3390/ijms231710070
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author Helmstädter, Moritz
Schierle, Simone
Isigkeit, Laura
Proschak, Ewgenij
Marschner, Julian Aurelio
Merk, Daniel
author_facet Helmstädter, Moritz
Schierle, Simone
Isigkeit, Laura
Proschak, Ewgenij
Marschner, Julian Aurelio
Merk, Daniel
author_sort Helmstädter, Moritz
collection PubMed
description Fatty acid mimetics (FAM) are bioactive molecules acting through the binding sites of endogenous fatty acid metabolites on enzymes, transporters, and receptors. Due to the special characteristics of these binding sites, FAMs share common chemical features. Pharmacological modulation of fatty acid signaling has therapeutic potential in multiple pathologies, and several FAMs have been developed as drugs. We aimed to elucidate the promiscuity of FAM drugs on lipid-activated transcription factors and tested 64 approved compounds for activation of RAR, PPARs, VDR, LXR, FXR, and RXR. The activity screening revealed nuclear receptor agonism of several FAM drugs and considerable promiscuity of NSAIDs, while other compound classes evolved as selective. These screening results were not anticipated by three well-established target prediction tools, suggesting that FAMs are underrepresented in bioactivity data for model development. The screening dataset may therefore valuably contribute to such tools. Oxaprozin (RXR), tianeptine (PPARδ), mycophenolic acid (RAR), and bortezomib (RAR) exhibited selective agonism on one nuclear receptor and emerged as attractive leads for the selective optimization of side activities. Additionally, their nuclear receptor agonism may contribute relevant and valuable polypharmacology.
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spelling pubmed-94560862022-09-09 Activity Screening of Fatty Acid Mimetic Drugs Identified Nuclear Receptor Agonists Helmstädter, Moritz Schierle, Simone Isigkeit, Laura Proschak, Ewgenij Marschner, Julian Aurelio Merk, Daniel Int J Mol Sci Article Fatty acid mimetics (FAM) are bioactive molecules acting through the binding sites of endogenous fatty acid metabolites on enzymes, transporters, and receptors. Due to the special characteristics of these binding sites, FAMs share common chemical features. Pharmacological modulation of fatty acid signaling has therapeutic potential in multiple pathologies, and several FAMs have been developed as drugs. We aimed to elucidate the promiscuity of FAM drugs on lipid-activated transcription factors and tested 64 approved compounds for activation of RAR, PPARs, VDR, LXR, FXR, and RXR. The activity screening revealed nuclear receptor agonism of several FAM drugs and considerable promiscuity of NSAIDs, while other compound classes evolved as selective. These screening results were not anticipated by three well-established target prediction tools, suggesting that FAMs are underrepresented in bioactivity data for model development. The screening dataset may therefore valuably contribute to such tools. Oxaprozin (RXR), tianeptine (PPARδ), mycophenolic acid (RAR), and bortezomib (RAR) exhibited selective agonism on one nuclear receptor and emerged as attractive leads for the selective optimization of side activities. Additionally, their nuclear receptor agonism may contribute relevant and valuable polypharmacology. MDPI 2022-09-03 /pmc/articles/PMC9456086/ /pubmed/36077469 http://dx.doi.org/10.3390/ijms231710070 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
Helmstädter, Moritz
Schierle, Simone
Isigkeit, Laura
Proschak, Ewgenij
Marschner, Julian Aurelio
Merk, Daniel
Activity Screening of Fatty Acid Mimetic Drugs Identified Nuclear Receptor Agonists
title Activity Screening of Fatty Acid Mimetic Drugs Identified Nuclear Receptor Agonists
title_full Activity Screening of Fatty Acid Mimetic Drugs Identified Nuclear Receptor Agonists
title_fullStr Activity Screening of Fatty Acid Mimetic Drugs Identified Nuclear Receptor Agonists
title_full_unstemmed Activity Screening of Fatty Acid Mimetic Drugs Identified Nuclear Receptor Agonists
title_short Activity Screening of Fatty Acid Mimetic Drugs Identified Nuclear Receptor Agonists
title_sort activity screening of fatty acid mimetic drugs identified nuclear receptor agonists
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9456086/
https://www.ncbi.nlm.nih.gov/pubmed/36077469
http://dx.doi.org/10.3390/ijms231710070
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