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

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.