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

Kizuku Miura; Michiko Fujihara; Masaki Watanabe; Yuta Takamura; Mayu Kawasaki; Shogo Nakano; Hiroki Kakuta

doi:10.1016/j.bmcl.2023.129536

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. Epub 2023 Oct 30.

Authors

Kizuku Miura¹, Michiko Fujihara², Masaki Watanabe³, Yuta Takamura³, Mayu Kawasaki⁴, Shogo Nakano⁴, Hiroki Kakuta⁵

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Ligands
Retinoid X Receptors* / metabolism

Substances

Retinoid X Receptors
Ligands