Discovery of Natural Products as Novel and Potent FXR Antagonists by Virtual Screening

Frontiers in Chemistry
Yanyan DiaoHonglin Li

Abstract

Farnesoid X receptor (FXR) is a member of nuclear receptor family involved in multiple physiological processes through regulating specific target genes. The critical role of FXR as a transcriptional regulator makes it a promising target for diverse diseases, especially those related to metabolic disorders such as diabetes and cholestasis. However, the underlying activation mechanism of FXR is still a blur owing to the absence of proper FXR modulators. To identify potential FXR modulators, an in-house natural product database (NPD) containing over 4,000 compounds was screened by structure-based virtual screening strategy and subsequent hit-based similarity searching method. After the yeast two-hybrid (Y2H) assay, six natural products were identified as FXR antagonists which blocked the CDCA-induced SRC-1 association. The IC50 values of compounds 2a, a diterpene bearing polycyclic skeleton, and 3a, named daphneone with chain scaffold, are as low as 1.29 and 1.79 μM, respectively. Compared to the control compound guggulsterone (IC50 = 6.47 μM), compounds 2a and 3a displayed 5- and 3-fold higher antagonistic activities against FXR, respectively. Remarkably, the two representative compounds shared low topological similarities with o...Continue Reading

References

Aug 1, 1994·Trends in Genetics : TIG·S Fields, R Sternglanz
May 21, 1999·Science·M MakishimaB Shan
Aug 24, 2000·Journal of Medicinal Chemistry·P R MaloneyT M Willson
May 4, 2002·Science·Nancy L UrizarDavid D Moore
Aug 9, 2002·Journal of Medicinal Chemistry·Roberto PellicciariTimothy M Willson
Dec 24, 2002·The Journal of Biological Chemistry·Isabelle DussaultBarry M Forman
Jan 28, 2003·Journal of Chemical Information and Computer Sciences·Yongping PanAlexander D MacKerell
Apr 30, 2003·Molecular Cell·Michael DownesRonald M Evans
Apr 30, 2003·Molecular Cell·Li-Zhi MiFraydoon Rastinejad
Dec 20, 2003·The Journal of Biological Chemistry·Jane-L LewJisong Cui
Mar 19, 2004·Journal of Medicinal Chemistry·Richard A FriesnerPeter S Shenkin
Mar 19, 2004·Journal of Medicinal Chemistry·Thomas A HalgrenJay L Banks
May 25, 2004·Journal of Chemical Information and Computer Sciences·Marcel L VerdonkPaul Watson
Nov 3, 2004·Nature Reviews. Drug Discovery·Douglas B KitchenJürgen Bajorath
Aug 19, 2005·Journal of Medicinal Chemistry·Roberto PellicciariStefano Fiorucci
Aug 16, 2006·Trends in Biochemical Sciences·Florence Y LeeYanqiao Zhang
Mar 31, 2007·Natural Product Research·W ZhangL Shan
Nov 9, 2007·Journal of Natural Products·Sang-Jip NamHeonjoong Kang
Nov 21, 2007·FEBS Letters·Yanqiao Zhang, Peter A Edwards
Apr 9, 2008·Proceedings of the National Academy of Sciences of the United States of America·Stephen M SoissonJoseph W Becker
May 6, 2008·The Journal of Steroid Biochemistry and Molecular Biology·Zhaohu LinXu Shen
Oct 1, 2008·Cell Research·Yan-Dong WangWendong Huang
Jan 7, 2009·Journal of Chemical Information and Modeling·Andreas BenderJohn W Davies
Nov 28, 2009·Current Medicinal Chemistry·Stefano FiorucciSabrina Cipriani
Dec 22, 2009·Bioorganic & Medicinal Chemistry·Xian-Wen YangWei-Dong Zhang
Dec 15, 2010·Journal of Natural Products·Hyukjae ChoiHeonjoong Kang
Oct 31, 2012·Journal of Asian Natural Products Research·Li-Bo WangLi-Jun Wu
Apr 24, 2013·Bioorganic & Medicinal Chemistry Letters·Xianwen CaoHonglin Li
Aug 29, 2013·Nature Reviews. Gastroenterology & Hepatology·Frank G SchaapPeter L M Jansen
Nov 13, 2014·Current Topics in Medicinal Chemistry·Andrea CarottiAntonio Macchiarulo
Oct 19, 2016·Journal of Digestive Diseases·Zhi Qing Yuan, Ke Wei Li
Aug 18, 2016·The New England Journal of Medicine·Frederik NevensUNKNOWN POISE Study Group
Sep 19, 2016·Gastroenterology·Frank J GonzalezAndrew D Patterson
Oct 25, 2016·Advances in Experimental Medicine and Biology·Takanori Yamada, Ken Sugimoto
Dec 3, 2016·Nucleic Acids Research·Anna GaultonAndrew R Leach
Mar 2, 2017·Digestive Diseases·C Daniel De Magalhaes FilhoRonald M Evans
Jul 2, 2017·Methods in Molecular Biology·Jer-Sheng Lin, Erh-Min Lai

❮ Previous
Next ❯

Citations

Nov 21, 2018·International Journal of Molecular Sciences·Manon GarciaClaude Beaudoin
May 31, 2019·Advances in Nutrition·Jose A Villa-RodriguezDiana E Roopchand
May 18, 2021·Computational and Structural Biotechnology Journal·Longying JiangYongheng Chen

❮ Previous
Next ❯

Methods Mentioned

BETA
two-hybrid
PCR
NMR
X-ray
Y2H

Software Mentioned

Glide XP
4WVD
SciTegic
Maestro
PocketShape
OPLS
Ligprep
Pipeline Pilot
QikProp
Glide

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.