2. Academic Validation
  3. Direct evaluation of polarity of the ligand binding pocket in retinoid X receptor using a fluorescent solvatochromic agonist

Direct evaluation of polarity of the ligand binding pocket in retinoid X receptor using a fluorescent solvatochromic agonist

  • Bioorg Med Chem Lett. 2023 Nov 15:96:129536. doi: 10.1016/j.bmcl.2023.129536.
Kizuku Miura 1,  Michiko Fujihara 2,  Masaki Watanabe 3,  Yuta Takamura 3,  Mayu Kawasaki 4,  Shogo Nakano 4,  Hiroki Kakuta 5
Affiliations

Affiliations

  • 1 Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1, Tsushima-naka, Kita-ku Okayama 700-8530, Japan.
  • 2 Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1, Tsushima-naka, Kita-ku Okayama 700-8530, Japan; Department of Liberal Arts, The Open University of Japan, 2-11 Wakaba, Mihama-ku, Chiba 261- 8586, Japan.
  • 3 Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1, Tsushima-naka, Kita-ku Okayama 700-8530, Japan.
  • 4 Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, 52- 1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
  • 5 Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1, Tsushima-naka, Kita-ku Okayama 700-8530, Japan. Electronic address: kakuta-h@okayama-u.ac.jp.
PMID: 37913851 DOI: 10.1016/j.bmcl.2023.129536
Abstract

High selectivity of small-molecule drug candidates for their target molecule is important to minimize potential side effects. One factor that contributes to the selectivity is the internal polarity of the ligand-binding pocket (LBP) in the target molecule, but this is difficult to measure. Here, we first confirmed that the retinoid X receptor (RXR) agonist 6-(ethyl(1-isobutyl-2-oxo-4-(trifluoromethyl)-1,2-dihydroquinolin-7-yl)amino)nicotinic acid (NEt-iFQ, 1) exhibits fluorescence solvatochromism, i.e., its Stokes shift depends on the polarity of the solvent, and then we utilized this property to directly measure the internal polarity of the RXRα-LBP. The Stokes shift of 1 when bound to the RXRα-LBP corresponded to that of 1 in chloroform solution. This finding is expected to be helpful for designing RXR-selective ligands. A similar approach should be appliable to evaluate the internal polarity of the LBPs of other receptors.

Keywords

Binding assay; Fluorescence; RXR; Solvatochromism.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-155437
    RXR Agonist