Amberlyst-15 catalysed synthesis of novel indole derivatives under ultrasound irradiation: Their evaluation as serotonin 5-HT2C receptor agonists

Reddy, Gangireddy Sujeevan; Kamaraj, Rajamanikkam; Hossain, Kazi Amirul; Kumar, J.S. Dileep; Thirupataiah, B.; Medishetti, Raghavender; Sri, N. Sushma; Misra, Parimal; Pal, Manojit

doi:10.1016/j.bioorg.2021.105380

Cited by 4 publications

(1 citation statement)

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“…For example, a 1700fold selective allosteric inhibition for phospholipase D1 (PLD1) compared to its subtype PLD2 has been reported [59]. Allosteric modulators may improve the efficacy and potency of an agonist (e.g., from 2 to 100-fold) in a receptor or may have a synergistic effect [60,61]. Furthermore, reciprocity or allosteric activation may occur [54], which means that the receptor is activated directly, without the presence of an orthosteric ligand [62].…”

Section: Allosteric Modulation Of Nuclear Receptorsmentioning

confidence: 99%

Allosteric Antagonism of the Pregnane X Receptor (PXR): Current-State-of-the-Art and Prediction of Novel Allosteric Sites

Kamaraj

Drastík

Maixnerová

et al. 2022

Cells

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The pregnane X receptor (PXR, NR1I2) is a xenobiotic-activated transcription factor with high levels of expression in the liver. It not only plays a key role in drug metabolism and elimination, but also promotes tumor growth, drug resistance, and metabolic diseases. It has been proposed as a therapeutic target for type II diabetes, metabolic syndrome, and inflammatory bowel disease, and PXR antagonists have recently been considered as a therapy for colon cancer. There are currently no PXR antagonists that can be used in a clinical setting. Nevertheless, due to the large and complex ligand-binding pocket (LBP) of the PXR, it is challenging to discover PXR antagonists at the orthosteric site. Alternative ligand binding sites of the PXR have also been proposed and are currently being studied. Recently, the AF-2 allosteric binding site of the PXR has been identified, with several compounds modulating the site discovered. Herein, we aimed to summarize our current knowledge of allosteric modulation of the PXR as well as our attempt to unlock novel allosteric sites. We describe the novel binding function 3 (BF-3) site of PXR, which is also common for other nuclear receptors. In addition, we also mention a novel allosteric site III based on in silico prediction. The identified allosteric sites of the PXR provide new insights into the development of safe and efficient allosteric modulators of the PXR receptor. We therefore propose that novel PXR allosteric sites might be promising targets for treating chronic metabolic diseases and some cancers.

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