Molecular docking, dynamics, and pharmacology studies on bexarotene as an agonist of ligand-activated transcription factors, retinoid X receptors

Nitin Chitranshi, Yogita Dheer, Sanjay Kumar, Stuart L. Graham, Vivek Gupta

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Retinoid X receptors (RXRs) belong to the nuclear receptor superfamily, and upon ligand activation, these receptors control gene transcription via either homodimerization with themselves or heterodimerization with the partner-nuclear receptor. The protective effects of RXRs and RXR agonists have been reported in several neurodegenerative diseases, including in the retina. This study was aimed to prioritize compounds from natural and synthetic origin retinoids as potential RXR agonists by molecular docking and molecular dynamic simulation strategies. The docking studies indicated bexarotene as a lead compound that can activate various RXR receptor isoforms (α, β, and γ) and has a strong binding affinity to the receptor protein than retinoic acid, which is known as a natural endogenous RXR agonist. Dynamic simulation studies confirmed that the hydrogen bonding and hydrophobic interactions were highly stable in all the three isoforms of the RXR-bexarotene complex. To further validate the significance of the RXR receptor in neurons, in vitro pharmacological treatment of neuronal SH-SY5Y cells with bexarotene was performed. In vitro data from SH-SY5Y cells confirmed that bexarotene activated RXR-simulated neurite outgrowth significantly. We conclude that bexarotene could be potentially used as an exogenous activator of RXRs and emerge as a good drug target for several neurodegenerative disorders.

LanguageEnglish
Pages11745-11760
Number of pages16
JournalJournal of Cellular Biochemistry
Volume120
Issue number7
Early online date11 Feb 2019
DOIs
Publication statusPublished - 1 Jul 2019

Fingerprint

Retinoid X Receptors
Molecular Dynamics Simulation
Transcription Factors
Pharmacology
Ligands
Cytoplasmic and Nuclear Receptors
Neurodegenerative Diseases
Protein Isoforms
factor X receptors
bexarotene
Neurodegenerative diseases
Lead compounds
Retinoic Acid Receptors
Retinoids
Computer simulation
Hydrogen Bonding
Transcription
Tretinoin
Hydrophobic and Hydrophilic Interactions
Neurons

Keywords

  • bexarotene
  • docking
  • molecular dynamics
  • retinoic acid
  • retinoid X receptors

Cite this

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abstract = "Retinoid X receptors (RXRs) belong to the nuclear receptor superfamily, and upon ligand activation, these receptors control gene transcription via either homodimerization with themselves or heterodimerization with the partner-nuclear receptor. The protective effects of RXRs and RXR agonists have been reported in several neurodegenerative diseases, including in the retina. This study was aimed to prioritize compounds from natural and synthetic origin retinoids as potential RXR agonists by molecular docking and molecular dynamic simulation strategies. The docking studies indicated bexarotene as a lead compound that can activate various RXR receptor isoforms (α, β, and γ) and has a strong binding affinity to the receptor protein than retinoic acid, which is known as a natural endogenous RXR agonist. Dynamic simulation studies confirmed that the hydrogen bonding and hydrophobic interactions were highly stable in all the three isoforms of the RXR-bexarotene complex. To further validate the significance of the RXR receptor in neurons, in vitro pharmacological treatment of neuronal SH-SY5Y cells with bexarotene was performed. In vitro data from SH-SY5Y cells confirmed that bexarotene activated RXR-simulated neurite outgrowth significantly. We conclude that bexarotene could be potentially used as an exogenous activator of RXRs and emerge as a good drug target for several neurodegenerative disorders.",
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Molecular docking, dynamics, and pharmacology studies on bexarotene as an agonist of ligand-activated transcription factors, retinoid X receptors. / Chitranshi, Nitin; Dheer, Yogita; Kumar, Sanjay; Graham, Stuart L.; Gupta, Vivek.

In: Journal of Cellular Biochemistry, Vol. 120, No. 7, 01.07.2019, p. 11745-11760.

Research output: Contribution to journalArticleResearchpeer-review

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