Movatterモバイル変換

[0]ホーム
URL:

Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
Thehttps:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

NIH NLM Logo
Log inShow account info
Access keysNCBI HomepageMyNCBI HomepageMain ContentMain Navigation
pubmed logo
Advanced Clipboard
User Guide

Full text links

MDPI full text link MDPI Free PMC article
Full text links

Actions

.2022 Sep 3;23(17):10070.
doi: 10.3390/ijms231710070.

Activity Screening of Fatty Acid Mimetic Drugs Identified Nuclear Receptor Agonists

Affiliations

Activity Screening of Fatty Acid Mimetic Drugs Identified Nuclear Receptor Agonists

Moritz Helmstädter et al. Int J Mol Sci..

Abstract

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.

Keywords: bortezomib; mycophenolate; oxaprozin; polypharmacology; selective optimization of side activities; tianeptine; transcription factor.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Fatty acid mimetic (FAM) drug library screening. (a) Despite their common fatty acid mimetic architecture, the screened FAM drugs displayed high chemical diversity. The heatmap shows the pairwise Tanimoto similarity computed on Morgan fingerprints [17]. (b) Results of the primary screening of FAM drugs on eight nuclear receptors. Heatmap shows the mean fold nuclear receptor activation,n = 2. Compounds causing ≥ 5-fold activation were considered active. (c) The screening results indicated different promiscuity of nuclear receptors in terms of tolerated FAM ligands. PPARγ was activated by the greatest number of FAMs, while only a few hits were retrieved for PPARδ and FXR. (d) The screening revealed promiscuity of NSAIDs and retinoids among nuclear receptors, while ACE inhibitors and prostanoid analogues were highly selective.
Figure 2
Figure 2
Molecular features of the screening hits. (a) The activity screening yielded structurally novel and chemically diverse hits for six nuclear receptors. (b) FAM drugs active on nuclear receptors had a higher logP, a lower PSA, less HBA and HBD, less rotatable bonds, and a lower Csp3 fraction than the inactive compounds. *p < 0.05, **p < 0.01, ***p < 0.001 (t-test). (c) The target prediction tools SuperPred [19], SwissTargetPrediction [20], and SEA [21] did not reproduce the screening results, suggesting that the dataset is a valuable addition for model training.
Figure 3
Figure 3
Predicted interactions of tianeptine (green), mycophenolic acid (yellow), and bortezomib (cyan) with their respective nuclear receptor targets. Docking was performed in MOE using X-ray structures of the PPARδ LBD (pdb ID: 1GWX [25]) and the RARα LBD (pdb ID: 3KMZ) [26] as templates. Co-crystalized reference ligands (PPARδ: magenta—GW2433; cyan—L165041; rose—GW501516; and yellow—GW0742; RARα: magenta—BMS493; brown—Ro 40-6055; and green—BMS614) are shown for comparison.
Figure 4
Figure 4
Mycophenolic acid and bortezomib activated transcriptional activity via the human RAR response element (RARE). Data are the mean ± S.E.M.,n = 3. *p < 0.05, **p < 0.01, ***p < 0.001 (t-test vs. DMSO).
See this image and copyright information in PMC

References

    1. De Carvalho C.C.C.R., Caramujo M.J. The Various Roles of Fatty Acids. Molecules. 2018;23:2583. doi: 10.3390/molecules23102583. - DOI - PMC - PubMed
    1. Proschak E., Heitel P., Kalinowsky L., Merk D. Opportunities and Challenges for Fatty Acid Mimetics in Drug Discovery. J. Med. Chem. 2017;60:5235–5266. doi: 10.1021/acs.jmedchem.6b01287. - DOI - PubMed
    1. Iyer A., Fairlie D.P., Prins J.B., Hammock B.D., Brown L. Inflammatory lipid mediators in adipocyte function and obesity. Nat. Rev. Endocrinol. 2010;6:71–82. doi: 10.1038/nrendo.2009.264. - DOI - PubMed
    1. Calder P.C. Fatty acids and inflammation: The cutting edge between food and pharma. Eur. J. Pharmacol. 2011;668:S50–S58. doi: 10.1016/j.ejphar.2011.05.085. - DOI - PubMed
    1. Proschak E., Stark H., Merk D. Polypharmacology by Design: A Medicinal Chemist’s Perspective on Multitargeting Compounds. J. Med. Chem. 2019;62:420–444. doi: 10.1021/acs.jmedchem.8b00760. - DOI - PubMed

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full text links
MDPI full text link MDPI Free PMC article
Cite
Send To

NCBI Literature Resources

MeSHPMCBookshelfDisclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

[8]ページ先頭
©2009-2025 Movatter.jp